Picornavirus subversion of the autophagy pathway

While autophagy has been shown to act as an anti-viral defense, the Picornaviridae avoid and, in many cases, subvert this pathway to promote their own replication. Evidence indicates that some picornaviruses hijack autophagy in order to induce autophagosome-like membrane structures for genomic RNA replication. Expression of picornavirus proteins can specifically induce the machinery of autophagy, although the mechanisms by which the viruses employ autophagy appear to differ. Many picornaviruses up-regulate autophagy in order to promote viral replication while some members of the family also inhibit degradation by autolysosomes. Here we explore the unusual relationship of this medically important family of viruses with a degradative mechanism of innate immunity.     

Conserved role for autophagy in Rho1-mediated cortical remodeling and blood cell recruitment

Dynamic regulation of cell shape underlies many developmental and immune functions. Cortical remodeling is achieved under the central control of Rho GTPase pathways that modulate an exquisite balance in the dynamic assembly and disassembly of the cytoskeleton and focal adhesions. Macroautophagy (autophagy), associated with bulk cytoplasmic remodeling through lysosomal degradation, has clearly defined roles in cell survival and death. Moreover, it is becoming apparent that proteins, organelles, and pathogens can be targeted for autophagic clearance by selective mechanisms, although the extent and roles of such degradation are unclear. Here we report a conserved role for autophagy specifically in the cortical remodeling of Drosophila blood cells (hemocytes) and mouse macrophages. Continuous autophagy was required for integrin-mediated hemocyte spreading and Rho1-induced cell protrusions. Consequently, hemocytes disrupted for autophagy were impaired in their recruitment to epidermal wounds. Cell spreading required ref(2)P, the Drosophila p62 multiadaptor, implicating selective autophagy as a novel mechanism for modulating cortical dynamics. These results illuminate a specific and conserved role for autophagy as a regulatory mechanism for cortical remodeling, with implications for immune cell function.     

Autophagy Inhibits Intercellular Transport of Citrus Leaf Blotch Virus by Targeting Viral Movement Protein

Autophagy is an evolutionarily conserved cellular-degradation mechanism implicated in antiviral defense in plants. Studies have shown that autophagy suppresses virus accumulation in cells; however, it has not been reported to specifically inhibit viral spread in plants. This study demonstrated that infection with citrus leaf blotch virus (CLBV; genus Citrivirus, family Betaflexiviridae) activated autophagy in Nicotiana benthamiana plants as indicated by the increase of autophagosome formation. Impairment of autophagy through silencing of N. benthamiana autophagy-related gene 5 (NbATG5) and NbATG7 enhanced cell-to-cell and systemic movement of CLBV; however, it did not affect CLBV accumulation when the systemic infection had been fully established. Treatment using an autophagy inhibitor or silencing of NbATG5 and NbATG7 revealed that transiently expressed movement protein (MP), but not coat protein, of CLBV was targeted by selective autophagy for degradation. Moreover, we identified that CLBV MP directly interacted with NbATG8C1 and NbATG8i, the isoforms of autophagy-related protein 8 (ATG8), which are key factors that usually bind cargo receptors for selective autophagy. Our results present a novel example in which autophagy specifically targets a viral MP to limit the intercellular spread of the virus in plants.     

Membrane recruitment of autophagy proteins in selective autophagy

Autophagy is a stress response that is upregulated in response to signals such as starvation, growth factor deprivation, endoplasmic reticulum stress, and pathogen infection. Defects in this pathway are the underlying cause of a number of diseases, including metabolic aberrations, infectious diseases, and cancer, which are closely related to hepatic disorders. To date, more than 30 human ATG (autophagy) genes have been reported to regulate autophagosome formation. In this review, we summarize the current understanding of how ATG proteins behave during autophagosome formation in both non-selective and selective autophagy.     

Autophagy in ethanol-exposed liver disease

Ethanol metabolism in hepatocytes causes the generation of reactive oxygen species, endoplasmic reticulum stress and alterations in mitochondrial energy and REDOX metabolism. In ethanol-exposed liver disease, autophagy not only acts as a cleanser to remove damaged organelles and cytosolic components, but also selectively clears specific targets such as lipid droplets and damaged mitochondria. Moreover, ethanol appears to play a role in protecting hepatocytes from apoptosis at certain concentrations. This article describes the evidence, function and potential mechanism of autophagy in ethanol-exposed liver disease and the controversy surrounding the effects of ethanol on autophagy.     

The Emerging Roles of Viroporins in ER Stress Response and Autophagy Induction during Virus Infection

Viroporins are small hydrophobic viral proteins that oligomerize to form aqueous pores on cellular membranes. Studies in recent years have demonstrated that viroporins serve important functions during virus replication and contribute to viral pathogenicity. A number of viroporins have also been shown to localize to the endoplasmic reticulum (ER) and/or its associated membranous organelles. In fact, replication of most RNA viruses is closely linked to the ER, and has been found to cause ER stress in the infected cells. On the other hand, autophagy is an evolutionarily conserved “self-eating” mechanism that is also observed in cells infected with RNA viruses. Both ER stress and autophagy are also known to modulate a wide variety of signaling pathways including pro-inflammatory and innate immune response, thereby constituting a major aspect of host-virus interactions. In this review, the potential involvement of viroporins in virus-induced ER stress and autophagy will be discussed.     

The Autophagy Cargo Receptor SQSTM1 Inhibits Infectious Bursal Disease Virus Infection through Selective Autophagic Degradation of Double-Stranded Viral RNA

Selective autophagy mediates the degradation of cytoplasmic cargos, such as damaged organelles, invading pathogens, and protein aggregates. However, whether it targets double-stranded RNA (dsRNA) of intracellular pathogens is still largely unknown. Here, we show that selective autophagy regulates the degradation of the infectious bursal disease virus (IBDV) dsRNA genome. The amount of dsRNA decreased greatly in cells that overexpressed the autophagy-required protein VPS34 or autophagy cargo receptor SQSTM1, while it increased significantly in SQSTM1 or VPS34 knockout cells or by treating wild-type cells with the autophagy inhibitor chloroquine or wortmannin. Confocal microscopy and structured illumination microscopy showed SQSTM1 colocalized with dsRNA during IBDV infection. A pull-down assay further confirmed the direct binding of SQSTM1 to dsRNA through amino acid sites R139 and K141. Overexpression of SQSTM1 inhibited the replication of IBDV, while knockout of SQSTM1 promoted IBDV replication. Therefore, our findings reveal the role of SQSTM1 in clearing viral dsRNA through selective autophagy, highlighting the antiviral role of autophagy in the removal of the viral genome.     

Mosquito Immunity against Arboviruses

Arthropod-borne viruses (arboviruses) pose a significant threat to global health, causing human disease with increasing geographic range and severity. The recent availability of the genome sequences of medically important mosquito species has kick-started investigations into the molecular basis of how mosquito vectors control arbovirus infection. Here, we discuss recent findings concerning the role of the mosquito immune system in antiviral defense, interactions between arboviruses and fundamental cellular processes such as apoptosis and autophagy, and arboviral suppression of mosquito defense mechanisms. This knowledge provides insights into co-evolutionary processes between vector and virus and also lays the groundwork for the development of novel arbovirus control strategies that target the mosquito vector.     

神经元自噬在缺血缺氧性脑损伤中的作用

自噬是广泛存在于真核细胞中通过溶酶体机制降解自身成分的一种代谢途径.自噬不仅可通过激活经典的自噬小体-溶酶体途径,而且还可通过影响凋亡和坏死的发生、发展对细胞死亡进行调控.目前,自噬在急性脑缺血缺氧后神经元损伤方面的作用及其具体机制尚不明确.研究表明,缺血缺氧后的自噬具有神经保护作用,如维持神经元稳态、减少神经元死亡等;但也有研究认为,自噬能通过激活多种通路加重缺血缺氧后神经元损伤,甚至诱导神经元死亡.     

Viruses, autophagy genes, and Crohn's disease

The etiology of the intestinal disease Crohn's disease involves genetic factors as well as ill-defined environmental agents. Several genetic variants linked to this disease are associated with autophagy, a process that is critical for proper responses to viral infections. While a role for viruses in this disease remains speculative, accumulating evidence indicate that this possibility requires serious consideration. In this review, we will examine the three-way relationship between viruses, autophagy genes, and Crohn's disease and discuss how host-pathogen interactions can mediate complex inflammatory disorders.     

Selective autophagy of AKAP11 activates cAMP/PKA to fuel mitochondrial metabolism and tumor cell growth

Autophagy is a catabolic pathway that provides self-nourishment and maintenance of cellular homeostasis. Autophagy is a fundamental cell protection pathway through metabolic recycling of various intracellular cargos and supplying the breakdown products. Here, we report an autophagy function in governing cell protection during cellular response to energy crisis through cell metabolic rewiring. We observe a role of selective type of autophagy in direct activation of cyclic AMP protein kinase A (PKA) and rejuvenation of mitochondrial function. Mechanistically, autophagy selectively degrades the inhibitory subunit RI of PKA holoenzyme through A-kinase–anchoring protein (AKAP) 11. AKAP11 acts as an autophagy receptor that recruits RI to autophagosomes via LC3. Glucose starvation induces AKAP11-dependent degradation of RI, resulting in PKA activation that potentiates PKA-cAMP response element-binding signaling, mitochondria respiration, and ATP production in accordance with mitochondrial elongation. AKAP11 deficiency inhibits PKA activation and impairs cell survival upon glucose starvation. Our results thus expand the view of autophagy cytoprotection mechanism by demonstrating selective autophagy in RI degradation and PKA activation that fuels the mitochondrial metabolism and confers cell resistance to glucose deprivation implicated in tumor growth.

Macroautophagy (henceforth autophagy) is a catabolic process that degrades various cellular cargos through lysosomes. The autophagy process includes the formation and trafficking of autophagosomes, which sequester the cellular cargos destined for the clearance. Autophagy is activated in response to nutrient deprivation or cellular injuries and serves as a recycling mechanism that maintains cellular homeostasis through degradation of cytoplasmic components. Autophagy provides cell self-nourishment and supports cellular metabolism by supplying breakdown products (1, 2); therefore, autophagy is a fundamental cell protection mechanism. Whether autophagy has a direct function beyond recycling of the breakdown molecules to maintain metabolic homeostasis and cell survival, however, is poorly understood. In certain cancer types, autophagy plays an important role in sustaining the aggressive growth of the tumor cells by enhancing cell metabolism. Although our group and others have previously shown an inhibitory function of Beclin 1–mediated autophagy in tumorigenesis (3, 4), the current view is that tumors, once established, rely heavily on autophagy to survive due to high metabolic demand. One potential mechanism is that the metabolic products generated by autophagy provide tumor cells with metabolic rewiring that enables them to survive even under nutrient-poor conditions (5, 6). However, it remains unclear whether autophagy plays a role beyond the production of metabolic fuel sources to maintain metabolic plasticity and tumor cell growth.Available evidence has demonstrated the selectivity of autophagy in the digestion of certain cellular cargoes mediated by autophagy adaptors/receptors. Characterization of the autophagy adaptors has shed light on the versatile physiological function of autophagy in the maintenance of the homeostasis for large molecules and cellular organelles (7, 8). These adaptors recognize and recruit selective cargos to autophagy machinery for degradation through direct interaction with yeast autophagy gene Atg8 homologs of mammalian LC3/GABARAP/Gate16 proteins. While a few autophagy receptors have been reported, it is clear that many more are yet to be identified (7, 8).The best-known signaling pathways that control the metabolic stress-induced autophagy are mediated by mTOR and AMPK kinases, both of which are the master regulators for cellular metabolism (9, 10). Cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA) is also a key kinase of cell metabolism that governs diverse cellular pathways, including cellular glucose metabolism and bioenergetic processes (11–13). Surprisingly, whether and how cAMP/PKA regulates autophagy or vice versa is poorly understood in mammals (14–16). cAMP/PKA signaling has emerged over recent years as a key regulator for mitochondrial functions, highlighting the mechanism of cAMP/PKA in cellular metabolism control (17, 18). Despite an established role for PKA in the regulation of mitochondrial metabolism, whether autophagy and PKA converge to regulate metabolic reprogramming and cell survival remains unknown.The PKA holoenzyme consists of two regulatory subunits (R) and two catalytic subunits (C). The R subunits are inhibitory of catalytic kinase activity; upon binding to cAMP, the R subunit dissociates from C subunit, resulting in activation of PKA (19). Furthermore, the specific cellular functions of PKA are controlled by a number of A-kinase–anchoring proteins (AKAPs). The AKAPs bind the R subunits and restrict the PKA holoenzyme to various intracellular compartments, providing spatiotemporal regulation of PKA activity (20). However, the functions of many AKAPs are poorly characterized.Here, we report a role of autophagy that controls cellular metabolism beyond the production of metabolic sources—it activates cAMP/PKA kinase activity by selective degradation of the inhibitory subunit of R1α through autophagy receptor AKAP11 in response to glucose starvation. AKAP11-mediated cAMP/PKA activation leads to elevation of mitochondrial metabolism and cell protection. Our study reveals a previously unrecognized function of autophagy in metabolic rewiring of cells that promote cell survival under energy crisis. Our study thus suggests that selective autophagy induced RI degradation and PKA activation may contribute to the resistance of tumor cells to metabolic stress.     

Fatty acid synthase is preferentially degraded by autophagy upon nitrogen starvation in yeast

Autophagy, an evolutionarily conserved intracellular catabolic process, leads to the degradation of cytosolic proteins and organelles in the vacuole/lysosome. Different forms of selective autophagy have recently been described. Starvation-induced protein degradation, however, is considered to be nonselective. Here we describe a novel interaction between autophagy-related protein 8 (Atg8) and fatty acid synthase (FAS), a pivotal enzymatic complex responsible for the entire synthesis of C16- and C18-fatty acids in yeast. We show that although FAS possesses housekeeping functions, under starvation conditions it is delivered to the vacuole for degradation by autophagy in a Vac8- and Atg24-dependent manner. We also provide evidence that FAS degradation is essential for survival under nitrogen deprivation. Our results imply that during nitrogen starvation specific proteins are preferentially recruited into autophagosomesAutophagy is a major cellular catabolic pathway in eukaryotes, responsible for the degradation of organelles and large protein aggregates. This process is induced under various stress conditions, such as amino acid starvation, hypoxia, and oxidative stress (1, 2).In yeast (Saccharomyces cerevisiae), nitrogen starvation is known to induce macroautophagy (hereafter termed autophagy), which is essential mainly for supplementing amino acids needed for protein synthesis (3). Autophagy has long been considered to be a nonselective process except for the recruitment of ribosomes into autophagosomes, which was suggested to be selective under conditions of nitrogen starvation (4). Selective autophagy is thought to play a role mainly in cell homeostasis, and it uses the core autophagy genes and varying sets of proteins for different cargos (5). Autophagy-related protein 8 (Atg8), a key autophagic factor essential for autophagosome biogenesis, also plays a major role in selective autophagy by recruiting cargo proteins into the autophagosome (6).Fatty acid synthase (FAS) is a large (2.6 MDa), essential enzymatic complex responsible for the entire synthesis of C16- and C18-fatty acids (7). FAS is composed of two subunits, Fas1 (Fasβ) and Fas2 (Fasα), which are arranged in an α₆β₆ macromolecular complex. Deletion of one of the FAS subunits has been shown to result in degradation of the other (8). Whereas the unassembled Fas2 subunit is short-lived and degrades in the proteasome, the unassembled Fas1, once induced, is degraded by autophagy. Moreover, the FAS complex is known to be delivered to the vacuole under potassium acetate starvation (8).Here we investigated the role of autophagy in the degradation of the FAS complex. We report a physical interaction between Atg8 and FAS, and show that autophagy preferentially degrades FAS and decreases its activity during nitrogen starvation. We suggest that the selective degradation of FAS under nitrogen starvation requires the participation of Atg24 and Vac8, two factors that each play a role in selective autophagy (9–12). Finally, we show that FAS degradation is important for cell viability. We propose that selective degradation of proteins under nitrogen starvation occurs to maintain cell homeostasis.     

Involvement of Autophagy in Coronavirus Replication

Coronaviruses are single stranded, positive sense RNA viruses, which induce the rearrangement of cellular membranes upon infection of a host cell. This provides the virus with a platform for the assembly of viral replication complexes, improving efficiency of RNA synthesis. The membranes observed in coronavirus infected cells include double membrane vesicles. By nature of their double membrane, these vesicles resemble cellular autophagosomes, generated during the cellular autophagy pathway. In addition, coronavirus infection has been demonstrated to induce autophagy. Here we review current knowledge of coronavirus induced membrane rearrangements and the involvement of autophagy or autophagy protein microtubule associated protein 1B light chain 3 (LC3) in coronavirus replication.     

A small-molecule scaffold induces autophagy in primary neurons and protects against toxicity in a Huntington disease model

Autophagy is an intracellular turnover pathway. It has special relevance for neurodegenerative proteinopathies, such as Alzheimer disease, Parkinson disease, and Huntington disease (HD), which are characterized by the accumulation of misfolded proteins. Although induction of autophagy enhances clearance of misfolded protein and has therefore been suggested as a therapy for proteinopathies, neurons appear to be less responsive to classic autophagy inducers than nonneuronal cells. Searching for improved inducers of neuronal autophagy, we discovered an N¹⁰-substituted phenoxazine that, at proper doses, potently and safely up-regulated autophagy in neurons in an Akt- and mTOR-independent fashion. In a neuron model of HD, this compound was neuroprotective and decreased the accumulation of diffuse and aggregated misfolded protein. A structure/activity analysis with structurally similar compounds approved by the US Food and Drug Administration revealed a defined pharmacophore for inducing neuronal autophagy. This pharmacophore should prove useful in studying autophagy in neurons and in developing therapies for neurodegenerative proteinopathies.     

Small-molecule enhancers of autophagy modulate cellular disease phenotypes suggested by human genetics

Studies of human genetics and pathophysiology have implicated the regulation of autophagy in inflammation, neurodegeneration, infection, and autoimmunity. These findings have motivated the use of small-molecule probes to study how modulation of autophagy affects disease-associated phenotypes. Here, we describe the discovery of the small-molecule probe BRD5631 that is derived from diversity-oriented synthesis and enhances autophagy through an mTOR-independent pathway. We demonstrate that BRD5631 affects several cellular disease phenotypes previously linked to autophagy, including protein aggregation, cell survival, bacterial replication, and inflammatory cytokine production. BRD5631 can serve as a valuable tool for studying the role of autophagy in the context of cellular homeostasis and disease.Macroautophagy (hereafter autophagy), an evolutionarily conserved catabolic process in which cytosolic content is engulfed and degraded in lysosomes, has been implicated in several human diseases, including inflammatory disorders such as Crohn’s disease (CD), immune responses to Mycobacterium tuberculosis (Mtb), α1-antitrypsin deficiency, nonalcoholic fatty liver disease, and neurodegenerative disorders (1). Autophagy is frequently initiated by ULK1-mediated phosphorylation of Beclin1, leading to activation of the lipid kinase VPS34, which in turn leads to engagement of two ubiquitin (Ub)-like conjugation systems that modify ATG12 and ATG8 (LC3) to trigger expansion of autophagosomal membranes (2). Once initiated, degradation by autophagy can be either nonselective for bulk intracellular components (canonical) or selective for cargo such as damaged organelles (mitophagy), invasive pathogens (xenophagy), or protein aggregates (aggrephagy) (3).Although many types of cells use autophagy, disease phenotypes linked to autophagy-related genes are often restricted primarily to specific organ systems. CD-associated genetic variants that regulate autophagy have been linked to phenotypes involving the intestinal epithelium and cytokine-producing innate immune cells that may reflect high microbial load. More specifically, disease-associated alleles in genes that regulate bacterial recognition (NOD2, IRGM) and autophagy (ATG16L1) are associated with reduced clearance of intracellular bacteria (4). Furthermore, expression of a coding variant in ATG16L1 (T300A) correlates with compromised bacterial defense, increased release of inflammatory cytokines (IL-1β), and reduced formation of antimicrobial granules in gut Paneth cells (5, 6). Similar organ-associated phenotypes have been observed for variants linked to other diseases. Mutations in the autophagy gene WDR45 have been associated with static encephalopathy of childhood with generation in adulthood (SENDA), and SENDA disease phenotypes (iron accumulation and cerebral atrophy) appear to be restricted to the brain despite WDR45 expression in skeletal muscle (7). Brain-related disease phenotypes have also been observed in patients with a form of hereditary spastic paraparesis bearing a recessive mutation in the putative autophagy regulator TECPR2, and in patients suffering from cerebellar atrophy associated with mutations in the autophagy modulator SNX14 (8, 9).Small-molecule enhancers of autophagy are increasingly being tested for their beneficial effects on disease phenotypes in relevant organ systems and cell types (10). For example, different enhancers exhibit distinct profiles of activity in innate and adaptive immune pathways, including host defense against pathogens (11). Phenothiazine-derived antipsychotics (prochlorperazine edisylate) and first-line antibiotics (isoniazid and pyrazinamide) promote autophagy-dependent activity against Mtb, the latter involving modulation of proinflammatory responses in Mtb-infected macrophages (12, 13). Likewise, the autophagy-inducing peptide Tat-Beclin1 enhances autophagy-dependent antiviral activity in cell and animal models (14). In the context of protein aggregation disorders, carbamazepine (CBZ)-induced autophagy reduces accumulation of α1-antitrypsin in liver cells and rescues hepatic fibrosis in mice (15), whereas rapamycin- or trehalose-induced autophagy clears α-synuclein and mutant huntingtin aggregates in neurodegenerative disease models, among others (16). Autophagy defects linked to the lysosomal storage disorder Niemann–Pick type C1 disease (NPC1; caused by mutation in the NPC1 protein) can be restored by stimulating autophagy with rapamycin or CBZ, which is cytoprotective in NPC1 disease-relevant cells (17, 18). In the context of CD, small molecules have been shown to promote favorable immune phenotypes. Treatment with the PDK1 inhibitor AR-12 in macrophages (19) or rapamycin in epithelial cells (20) promotes bacterial clearance, and treatment with rapamycin leads to reduced IL-1β levels in innate immune cells and animals, possibly via degradation of pro-IL-1β or its processing machinery (21).Though modulating the mTOR pathway appears to affect disease phenotypes in several contexts, mTOR signaling is also critical for nutrient sensing, cell growth, and other fundamental processes. For several reasons, it may be beneficial to avoid perturbation of this critical cellular pathway in treating disease; for example, its inhibition has also been linked to infection (22). Additional small molecules have been shown to induce autophagy independently of mTOR (e.g., trifluoperazine, niguldipine, ABT-737). These compounds span a range of annotated protein targets and signaling pathways, but the relevance of the annotated targets to promotion of autophagy often remains undefined and may in some cases constitute impediments for further development (1, 10). Identification of small-molecule modulators of canonical and selective autophagy in disease-relevant cell types with novel and distinct mechanisms of action will contribute to studying the relevance of autophagy in disease and the potential of autophagy enhancement as a therapeutic strategy.Here, we describe the identification of novel enhancers of autophagy using a high-throughput screen (HTS) of 59,541 small molecules prepared by stereoselective diversity-oriented chemical synthesis (23). We demonstrate that representative hits promote autophagy without perturbing mTOR signaling or lysosomal function, and display autophagy-dependent activity in a number of disease-relevant models, including suppression of NPC1-triggered apoptosis in human induced pluripotent stem cell (hiPSC)-derived neurons, enhancement of bacterial colocalization with autophagic markers and clearance in epithelial cells, and suppression of microbial product-mediated IL-1β secretion by macrophages. One probe, BRD5631, is capable of rescuing defects in bacterial colocalization with LC3 and suppressing IL-1β production in cells harboring the CD-associated allele of ATG16L1 (T300A). BRD5631 and related compounds constitute a novel set of mTOR-independent autophagy probes for studying the regulation of autophagy and its impact on disease pathways.     

Herpesviruses and autophagy: catch me if you can!

Autophagy is an evolutionarily conserved cellular degradation pathway involving the digestion of intracellular components via the lysosomal pathway. The autophagic pathway constitutively maintains cellular homeostasis by recycling cytoplasmic organelles and proteins, but it is also stimulated by environmental stress conditions, such as starvation, oxidative stress, and the accumulation of misfolded proteins. It also acts as a cellular defense mechanism against microorganisms by contributing to both the innate and adaptive immunity, and by eliminating intracellular pathogens (xenophagy). There is growing evidence that host cells try to control Herpesvirus infections by activating the autophagic machinery. However, it is well-known that Herpesviruses are smart pathogens and several, such as HSV-1, HCMV and HHV-8, are known to have developed numerous defense strategies for evading the host's immune response. Inhibition of the antiviral autophagic mechanism has also been reported. Autophagy has also been shown to enhance the major histocompatibility complex presentation of at least two viral proteins, the EBV-encoded EBNA-1 and the HSV-1 encoded gB. In this review, we present an overview of recent advances in our understanding of the complex interplay between autophagy and Herpesviruses.     

microRNA、细胞自噬与肝纤维化

近年来研究发现微小RNA（microRNA）在肝纤维化发生中起到重要调节作用,明晰miR表达谱的差别有助于揭示肝纤维化发生的分子调节机制、发现肝纤维化诊断的分子标志、并有助于发现新的治疗策略。此外研究还发现自噬（autophagy）信号在肝星状细胞（HSC）激活中起到重要作用,静息HSC通过自噬使含维生素A酯的脂滴释放和被利用,以此产生能量来驱动HSC的活化过程。该发现是肝纤维化发生机制的重要补充。     

细胞自噬在肝脏疾病中的作用

近年来,越来越多的证据表明细胞自噬在慢性肝炎病毒感染、酒精性肝病、脂肪肝等各种类型的肝脏疾病的发生发展中起到重要作用,成为关注和研究的新焦点。自噬是指细胞利用溶酶体大范围降解长寿命蛋白质、大分子物质、核糖体及受损细胞器的过程。简述了各种肝脏疾病与细胞自噬的关系,认为探索细胞自噬在肝病机制中所扮演的角色,将可能成为治疗肝脏疾病的一个新靶点。     

Fluorescent Protein-Based Autophagy Biosensors

Autophagy is an essential cellular process of self-degradation for dysfunctional or unnecessary cytosolic constituents and organelles. Dysregulation of autophagy is thus involved in various diseases such as neurodegenerative diseases. To investigate the complex process of autophagy, various biochemical, chemical assays, and imaging methods have been developed. Here we introduce various methods to study autophagy, in particular focusing on the review of designs, principles, and limitations of the fluorescent protein (FP)-based autophagy biosensors. Different physicochemical properties of FPs, such as pH-sensitivity, stability, brightness, spectral profile, and fluorescence resonance energy transfer (FRET), are considered to design autophagy biosensors. These FP-based biosensors allow for sensitive detection and real-time monitoring of autophagy progression in live cells with high spatiotemporal resolution. We also discuss future directions utilizing an optobiochemical strategy to investigate the in-depth mechanisms of autophagy. These cutting-edge technologies will further help us to develop the treatment strategies of autophagy-related diseases.