Scholarlink

<p>Protein Kinase A (PKA) is regulated spatially and temporally via scaffolding of its catalytic (Cα) and regulatory (RI/RII) subunits by the A-kinase-anchoring proteins (AKAP). By binding to an AKAP11 scaffold, PKA engages in poorly understood interactions with autophagy, a key degradation pathway for neuronal cell homeostasis. Mutations in AKAP11 promote schizophrenia and bipolar disorders (SZ-BP) through unknown mechanisms. Here, through proteomic-based analyses of immunopurified lysosomes, we identify the Cα-RIα-AKAP11 holocomplex as a prominent autophagy-associated protein-kinase complex. AKAP11 scaffolds Cα-RIα interaction with the autophagic machinery via its LC3-interacting region (LIR), enabling both PKA regulation by upstream signals, and its autophagy-dependent degradation. We identify Ser83 on the RIα linker-hinge region as an AKAP11-dependent phospho-residue that modulates RIα-Cα binding to the autophagosome and cAMP-induced PKA activation. Decoupling AKAP11-PKA from autophagy alters downstream phosphorylation events, supporting an autophagy-dependent checkpoint for PKA signaling. Ablating AKAP11 in induced pluripotent stem cell-derived neurons reveals dysregulation of multiple pathways for neuronal homeostasis. Thus, the autophagosome is a platform that modulates PKA signaling, providing a possible mechanistic link to SZ/BP pathophysiology.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Autophagosomes anchor an AKAP11-dependent regulatory checkpoint that shapes neuronal PKA signaling

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年4月22日

查看全文
  • Ashley Segura-Roman,
  • Y Rose Citron,
  • Myungsun Shin,
  • Nicole Sindoni,
  • Alex Maya-Romero,
  • Simon Rapp,
  • Claire Goul,
  • Joseph D Mancias,
  • Roberto Zoncu

摘要

Protein Kinase A (PKA) is regulated spatially and temporally via scaffolding of its catalytic (Cα) and regulatory (RI/RII) subunits by the A-kinase-anchoring proteins (AKAP). By binding to an AKAP11 scaffold, PKA engages in poorly understood interactions with autophagy, a key degradation pathway for neuronal cell homeostasis. Mutations in AKAP11 promote schizophrenia and bipolar disorders (SZ-BP) through unknown mechanisms. Here, through proteomic-based analyses of immunopurified lysosomes, we identify the Cα-RIα-AKAP11 holocomplex as a prominent autophagy-associated protein-kinase complex. AKAP11 scaffolds Cα-RIα interaction with the autophagic machinery via its LC3-interacting region (LIR), enabling both PKA regulation by upstream signals, and its autophagy-dependent degradation. We identify Ser83 on the RIα linker-hinge region as an AKAP11-dependent phospho-residue that modulates RIα-Cα binding to the autophagosome and cAMP-induced PKA activation. Decoupling AKAP11-PKA from autophagy alters downstream phosphorylation events, supporting an autophagy-dependent checkpoint for PKA signaling. Ablating AKAP11 in induced pluripotent stem cell-derived neurons reveals dysregulation of multiple pathways for neuronal homeostasis. Thus, the autophagosome is a platform that modulates PKA signaling, providing a possible mechanistic link to SZ/BP pathophysiology.