Receptor-mediated endocytosis 8 (RME-8)/DNAJC13 is a novel positive modulator of autophagy and stabilizes cellular protein homeostasis

被引：19

作者：

Besemer, Anna S. ^{[1
]}

Maus, Joanna ^{[1
]}

Ax, Mirjam D. A. ^{[1
]}

Stein, Anna ^{[1
]}

Vo, Stella ^{[1
]}

Freese, Christian ^{[1
]}

Nalbach, Karsten ^{[1
]}

von Hilchen, Christian ^{[1
]}

Pfalzgraf, Ines F. ^{[1
]}

Koziollek-Drechsler, Ingrid ^{[1
]}

Silva, Beate ^{[1
]}

Huesmann, Heike ^{[1
]}

Boukhallouk, Fatima ^{[2
]}

Florin, Luise ^{[3
,4
]}

Kern, Andreas ^{[1
]}

Behl, Christian ^{[1
]}

Clement, Albrecht M. ^{[1
]}

机构：

[1] Johannes Gutenberg Univ Mainz, Inst Pathobiochem, Univ Med Ctr, Duesbergweg 6, D-55128 Mainz, Germany

[2] Johannes Gutenberg Univ Mainz, Inst Med Microbiol & Hyg, Univ Med Ctr, D-55101 Mainz, Germany

[3] Johannes Gutenberg Univ Mainz, Inst Virol, Univ Med Ctr, D-55101 Mainz, Germany

[4] Johannes Gutenberg Univ Mainz, Res Ctr Immunotherapy FZI, Univ Med Ctr, D-55101 Mainz, Germany

来源：

CELLULAR AND MOLECULAR LIFE SCIENCES | 2021年 / 78卷 / 02期

关键词：

Proteostasis; RME-8; DNAJC13; Autophagy; ATG9A; Recycling endosome; C; elegans; J-DOMAIN PROTEIN; RECYCLING ENDOSOMES; ATG9A TRAFFICKING; WASH COMPLEX; MEMBRANE; RETROMER; RME-8; CLATHRIN; DISEASE; PROTEOSTASIS;

D O I：

10.1007/s00018-020-03521-y

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The cellular protein homeostasis (proteostasis) network responds effectively to insults. In a functional screen in C. elegans, we recently identified the gene receptor-mediated endocytosis 8 (rme-8; human ortholog: DNAJC13) as a component of the proteostasis network. Accumulation of aggregation-prone proteins, such as amyloid-beta 42 (A beta), alpha-synuclein, or mutant Cu/Zn-superoxide dismutase (SOD1), were aggravated upon the knockdown of rme-8/DNAJC13 in C. elegans and in human cell lines, respectively. DNAJC13 is involved in endosomal protein trafficking and associated with the retromer and the WASH complex. As both complexes have been linked to autophagy, we investigated the role of DNAJC13 in this degradative pathway. In knockdown and overexpression experiments, DNAJC13 acts as a positive modulator of autophagy. In contrast, the overexpression of the Parkinson's disease-associated mutant DNAJC13(N855S) did not enhance autophagy. Reduced DNAJC13 levels affected ATG9A localization at and its transport from the recycling endosome. As a consequence, ATG9A co-localization at LC3B-positive puncta under steady-state and autophagy-induced conditions is impaired. These data demonstrate a novel function of RME-8/DNAJC13 in cellular homeostasis by modulating ATG9A trafficking and autophagy.

引用

页码：645 / 660

页数：16

共 70 条

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