Selective autophagy of AKAP11 activates cAMP/PKA to fuel mitochondrial metabolism and tumor cell growth
Menée in vitro, cette étude met en évidence un mécanisme par lequel l'autophagie sélective, via l'activation de la voie de signalisation cAMP/PKA par la protéine AKAP11, alimente le métabolisme mitochondrial et la croissance des cellules cancéreuses
Autophagy is known to promote cell survival through providing various sources of fuels as a result of digestion. Here, we uncover a function of autophagy in cell metabolic regulation by directly activating cAMP/PKA signaling that fuels mitochondrial metabolism and confers cell resistance to energy crisis. We find that autophagy selectively degrades PKA inhibitory subunit RIα through new autophagy receptor AKAP11 in response to energy crisis, thus causing PKA activation, which is a central hub for a variety of cellular signaling. Our study suggests that tumor cells may exploit such a metabolic reprogramming mechanism for the oncogenic growth. We propose that AKAP11-mediated cAMP/PKA activation via selective autophagy should be explored in the future as a therapeutic target for cancer treatment.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.All study data are included in the article and/or SI Appendix.