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

Zhiqiang Deng, Xianting Li, Marian Blanca Ramirez, Kerry Purtell, Insup Choi, Jia Hong Lu, Qin Yu, Zhenyu Yue*

*Corresponding author for this work

Research output: Contribution to journalJournal articlepeer-review

24 Citations (Scopus)

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.

Original languageEnglish
Article numbere2020215118
Number of pages12
JournalProceedings of the National Academy of Sciences of the United States of America
Volume118
Issue number14
DOIs
Publication statusPublished - 6 Apr 2021

User-Defined Keywords

  • AKAP11
  • PKA
  • AUTOPHAGY
  • MITOCHONDRIAL METABOLISM
  • CELL SURVIVAL

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