SIP/CacyBP promotes autophagy by regulating levels of BRUCE/Apollon, which stimulates LC3-I degradation

Tian Xia Jiang, Jiang Bo Zou, Qian Qian Zhu, Cui Hua Liu, Guang Fei Wang, Ting Ting Du, Zi Yu Luo, Fang Guo, Lu Ming Zhou, Juan Juan Liu, Wensheng Zhang, You Sheng Shu, Li Yu, Peng Li, Ze'ev A. Ronai, Shu ichi Matsuzawa, Alfred L. Goldberg, Xiao Bo Qiu

Research output: Contribution to journalArticlepeer-review

39 Scopus citations

Abstract

BRUCE/Apollon is a membrane-associated inhibitor of apoptosis protein that is essential for viability and has ubiquitin-conjugating activity. On initiation of apoptosis, the ubiquitin ligase Nrdp1/RNF41 promotes proteasomal degradation of BRUCE. Here we demonstrate that BRUCE together with the proteasome activator PA28γ causes proteasomal degradation of LC3-I and thus inhibits autophagy. LC3-I on the phagophore membrane is conjugated to phosphatidylethanolamine to form LC3-II, which is required for the formation of autophagosomes and selective recruitment of substrates. SIP/CacyBP is a ubiquitination-related protein that is highly expressed in neurons and various tumors. Under normal conditions, SIP inhibits the ubiquitination and degradation of BRUCE, probably by blocking the binding of Nrdp1 to BRUCE. On DNA damage by topoisomerase inhibitors, Nrdp1 causes monoubiquitination of SIP and thus promotes apoptosis. However, on starvation, SIP together with Rab8 enhances the translocation of BRUCE into the recycling endosome, formation of autophagosomes, and degradation of BRUCE by optineurin-mediated autophagy. Accordingly, deletion of SIP in cultured cells reduces the autophagic degradation of damaged mitochondria and cytosolic protein aggregates. Thus, by stimulating proteasomal degradation of LC3-I, BRUCE also inhibits autophagy. Conversely, SIP promotes autophagy by blocking BRUCE-dependent degradation of LC3-I and by enhancing autophagosome formation and autophagic destruction of BRUCE. These actions of BRUCE and SIP represent mechanisms that link the regulation of autophagy and apoptosis under different conditions.

Original languageEnglish
Pages (from-to)13404-13413
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number27
DOIs
StatePublished - 2019
Externally publishedYes

Keywords

  • Apoptosis
  • Autophagy
  • BRUCE/Apollon
  • CacyBP/SIP
  • LC3

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