The Ubiquitin Receptor ADRM1 Modulates HAP40-Induced Proteasome Activity.
Huntington's disease (HD) is a progressive neurodegenerative disorder caused by an N-terminal expansion of polyglutamine stretch (polyQ) of huntingtin (Htt) protein. HAP40 is a huntingtin-associated protein with unknown cellular functions. Increased HAP40 expression has been reported in the brain of HD patients and HD mouse model. However, the relationship between the elevation of HAP40 and HD etiology remains elusive. In this study, we demonstrated that overexpression of HAP40 enhanced accumulation of mutant Htt aggregates and caused defects in proteasome function. Specifically, excess HAP40 interfered with adhesion-regulating molecule 1 (ADRM1), a proteasome ubiquitin receptor, to regulate the proteasome-dependent pathway. Increasing ADRM1 in the presence of excess HAP40 alleviated mutant Htt aggregates and at the same time, restored the cell viability. Reducing ADRM1 in the absence of excess HAP40; on the other hand, increased mutant Htt aggregates and decreased the cell viability. Our data provide compelling evidence to support that ADRM1 plays an important role in mediating removal of mutant Htt aggregates when excess HAP40 is present. ADRM1-dependent ubiquitin proteasome system (UPS) may be a general mechanism to guard cells from mutant Htt toxicity.
Department of Life Sciences, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, 70101, Taiwan.
Zih-Ning
ZN
Huang
Department of Life Sciences, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, 70101, Taiwan. lsher@mail.ncku.edu.tw.
Lu-Shiun
http://orcid.org/0000-0003-3665-6100
LS
Her
D000818:Animals; D002352:Carrier Proteins / Q000096:biosynthesis* / Q000235:genetics; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism*
C411807:Adrm1 protein, mouse; D002352:Carrier Proteins; D015815:Cell Adhesion Molecules; C428125:F8a protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex
Autophagy; Huntingtin-associated protein; Huntington’s disease (HD); Mutant huntingtin aggregates; Ubiquitin proteasome system; Ubiquitin receptor