USP19-Mediated Deubiquitination Facilitates the Stabilization of HRD1 Ubiquitin Ligase.
In the endoplasmic reticulum (ER), misfolded and unfolded proteins are eliminated by a process called ER-associated protein degradation (ERAD) in order to maintain cell homeostasis. In the ERAD pathway, several ER-localized E3 ubiquitin ligases target ERAD substrate proteins for ubiquitination and subsequent proteasomal degradation. However, little is known about how the functions of the ERAD ubiquitin ligases are regulated. Recently, USP19, an ER-anchored deubiquitinating enzyme (DUB), has been suggested to be involved in the regulation of ERAD. In this study, HRD1, an ERAD ubiquitin ligase, is shown to be a novel substrate for USP19. We demonstrate that USP19 rescues HRD1 from proteasomal degradation by deubiquitination of K48-linked ubiquitin chains. In addition, the altered expression of USP19 affects the steady-state levels of HRD1. These results suggest that USP19 regulates the stability of HRD1 and provide insight into the regulatory mechanism of the ERAD ubiquitin ligases.
Department of Life Science and Technology, Tokyo Institute of Technology, 4259-B13 Nagatsuta-cho, Midori-ku, Yokohama 226-8501, Japan. harada.k.ac@m.titech.ac.jp.
Kumi
K
Harada
Department of Life Science and Technology, Tokyo Institute of Technology, 4259-B13 Nagatsuta-cho, Midori-ku, Yokohama 226-8501, Japan. kato.m.ap@m.titech.ac.jp.
Masako
M
Kato
Department of Life Science and Technology, Tokyo Institute of Technology, 4259-B13 Nagatsuta-cho, Midori-ku, Yokohama 226-8501, Japan. nnakamur@bio.titech.ac.jp.
Nobuhiro
N
Nakamura
D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D010450:Endopeptidases / Q000235:genetics* / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D060746:Endoplasmic Reticulum-Associated Degradation; D057809:HEK293 Cells; D006801:Humans; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D055550:Protein Stability; D059748:Proteolysis; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D025801:Ubiquitin / Q000235:genetics* / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism; D054875:Ubiquitination
D034741:RNA, Small Interfering; D025801:Ubiquitin; C482345:SYVN1 protein, human; D044767:Ubiquitin-Protein Ligases; D010450:Endopeptidases; C559917:USP19 protein, human; D046988:Proteasome Endopeptidase Complex
ERAD; deubiquitinating enzyme; endoplasmic reticulum; membrane protein; ubiquitin ligase