The Cys-N-degron pathway modulates pexophagy through the N-terminal oxidation and arginylation of ACAD10
Creators: name: Shim, Sang Mi
name: Choi, Ha Rim
name: Kwon, Soon Chul
name: Kim, Hye Yeon
name: Sung, Ki Woon
name: Jung, Eui Jung
name: Mun, Su Ran
name: Bae, Tae Hyun
name: Kim, Dong Hyun
name: Son, Yeon Sung
name: Jung, Chan Hoon
name: Lee, Jihoon
name: Lee, Min Jae
name: Park, Joo-Won
name: Kwon, Yong Tae
Publisher: name: Taylor & Francis
Year: 2022
Subjects: subject: Biochemistry
subject: Microbiology
subject: FOS: Biological sciences
subject: Cell Biology
subject: Genetics
subject: 110309 Infectious Diseases
subject: FOS: Health sciences

description: In the N-degron pathway, N-recognins recognize cognate substrates for degradation via the ubiquitin (Ub)-proteasome system (UPS) or the autophagy-lysosome system (hereafter autophagy). We have recently shown that the autophagy receptor SQSTM1/p62 (sequestosome 1) is an N-recognin that binds the N-terminal arginine (Nt-Arg) as an N-degron to modulate autophagic proteolysis. Here, we show that the N-degron pathway mediates pexophagy, in which damaged peroxisomal fragments are degraded by autophagy under normal and oxidative stress conditions. This degradative process initiates when the Nt-Cys of ACAD10 (acyl-CoA dehydrogenase family, member 10), a receptor in pexophagy, is oxidized into Cys sulfinic (Cys<sup>O2</sup>) or sulfonic acid (Cys<sup>O3</sup>) by ADO (2-aminoethanethiol (cysteamine) dioxygenase). Under oxidative stress, the Nt-Cys of ACAD10 is chemically oxidized by reactive oxygen species (ROS). The oxidized Nt-Cys2 is arginylated by <i>ATE1</i>-encoded R-transferases, generating the RC<sup>OX</sup> N-degron. RC<sup>OX</sup>-ACAD10 marks the site of pexophagy via the interaction with PEX5 and binds the ZZ domain of SQSTM1/p62, recruiting LC3<sup>+</sup>-autophagic membranes. In mice, knockout of either <i>Ate1</i> responsible for Nt-arginylation or <i>Sqstm1/p62</i> leads to increased levels of peroxisomes. In the cells from patients with peroxisome biogenesis disorders (PBDs), characterized by peroxisomal loss due to uncontrolled pexophagy, inhibition of either ATE1 or SQSTM1/p62 was sufficient to recover the level of peroxisomes. Our results demonstrate that the Cys-N-degron pathway generates an N-degron that regulates the removal of damaged peroxisomal membranes along with their contents. We suggest that tannic acid, a commercially available drug on the market, has a potential to treat PBDs through its activity to inhibit ATE1 R-transferases. <b>Abbreviations:</b> ACAA1, acetyl-Coenzyme A acyltransferase 1; ACAD, acyl-Coenzyme A dehydrogenase; ADO, 2-aminoethanethiol (cysteamine) dioxygenase; ATE1, arginyltransferase 1; CDO1, cysteine dioxygenase type 1; ER, endoplasmic reticulum; LIR, LC3-interacting region; MOXD1, monooxygenase, DBH-like 1; NAC, N-acetyl-cysteine; Nt-Arg, N-terminal arginine; Nt-Cys, N-terminal cysteine; PB1, Phox and Bem1p; PBD, peroxisome biogenesis disorder; PCO, plant cysteine oxidase; PDI, protein disulfide isomerase; PTS, peroxisomal targeting signal; R-COX, Nt-Arg-CysOX; RNS, reactive nitrogen species; ROS, reactive oxygen species; SNP, sodium nitroprusside; UBA, ubiquitin-associated; UPS, ubiquitinproteasome system.