Neddylation-dependent RAB40-Cullin5 E3 ligase complex controls ubiquitin-mediated proteasomal degradation of DNAJC13.

Authors

Kazuki Sato, Naoto Sugeno, Takafumi Hasegawa, Shun Yoshida, Mitsunori Fukuda, Akemi Fujibayashi, Kiyotoshi Sekiguchi, Shun Ishiyama, Takaaki Nakamura, Ako Miyata, Satoshi Watanabe, Kensho Ikeda, Atsushi Takeda, Masashi Aoki

Published in

BBA advances. Volume 10. Pages 100200. Epub Aug 03, 2026.

Abstract

DNAJC13 is a member of DNAJ co-chaperone family and its missense mutation causes a rare familial form of Parkinson's disease. DNAJC13 is indispensable for neuronal homeostasis by regulation of autophagy and the regulation of receptor expression on the cell surface. However, the regulatory mechanisms governing DNAJC13 expression remain poorly understood. We previously demonstrated that DNAJC13 binds to RAB40 small GTPase. Unlike other RABs, RAB40 proteins interact with activated Cullin-5 (CUL5) via the SOCS box, forming an Cullin-RING E3 ubiquitin ligase (CRL) complex that regulates ubiquitylation of target proteins. Thus, as a binding partner of RAB40s, DNAJC13 degradation may be regulated by this functional complex. Here, we found that both N-and C-terminal regions of DNAJC13, including IWN1 and IWN3 domains, were essential for its binding to RAB40 A/B/C. Moreover, DNAJC13 degradation of relies predominantly on the ubiquitin-proteasome system rather than on autophagy, and upregulated DNAJC13 ubiquitination in the presence of RAB40A/B/C. Intriguingly, RNAi-mediated silencing of the RAB40 subfamily caused a significant increase in DNAJC13 expression, accompanied by higher autophagic flux. Furthermore, co-immunoprecipitation experiments demonstrated that RAB40C, which is predominantly expressed in midbrain dopaminergic neurons, binds to CUL5 and its activator NEDD8 as well as RBX2 (E2). Finally, DNAJC13 cellular levels were regulated by NEDD8 activity. Taken together, these findings indicate that NEDD8-mediated neddylation plays a key role in RAB40-CUL5-mediated DNAJC13 degradation.

PMID:
42602476
Bibliographic data and abstract were imported from PubMed on 15 Aug 2026.

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