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SEL1L degradation intermediates stimulate cytosolic aggregation of polyglutamine‐expanded protein
Author(s) -
Hattori Tokuya,
Hanafusa Ken,
Wada Ikuo,
Hosokawa Nobuko
Publication year - 2021
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.15761
Subject(s) - endoplasmic reticulum associated protein degradation , cytosol , endoplasmic reticulum , proteasome , microbiology and biotechnology , protein degradation , ubiquitin ligase , chemistry , huntingtin , biochemistry , ubiquitin , biology , unfolded protein response , gene , enzyme , mutant
Misfolded proteins in the endoplasmic reticulum (ER) are degraded by ER‐associated degradation (ERAD). In mammalian cells, the HRD1–SEL1L membrane ubiquitin ligase complex plays a central role in this process. However, SEL1L is inherently unstable, and excess SEL1L is also degraded by ERAD. Accordingly, when proteasome activity is inhibited, multiple degradation intermediates of SEL1L appear in the cytosol. In this study, we searched for factors that inhibit SEL1L degradation and identified OS‐9 and XTP3‐B, two ER lectins that regulate glycoprotein ERAD. SEL1L degradation was characterized by a ladder of degradation products, and the C‐terminal Pro‐rich region of SEL1L was responsible for generation of this pattern. In the cytosol, these degradation intermediates stimulated aggregation of polyglutamine‐expanded Huntingtin protein (Htt‐polyQ‐GFP) by interacting with aggregation‐prone proteins, including Htt‐polyQ‐GFP. Collectively, our findings indicate that peptide fragments of ER proteins generated during ERAD may affect protein aggregation in the cytosol, revealing the interconnection of protein homeostasis across subcellular compartments.