| Abstract: | 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. |
