TY - JOUR
T1 - The Ubiquitin Receptor ADRM1 Modulates HAP40-Induced Proteasome Activity
AU - Huang, Zih Ning
AU - Her, Lu Shiun
N1 - Funding Information:
We thank Dr. Lawrence S.B. Goldstein (University of California, San Diego, USA) for scientific insight and Dr. Su-Chiung Fang (Academia Sinica, Taiwan, R.O.C.) for critical reading of the manuscript and helpful discussion. We express our appreciation to Confocal Core facility at Academia Sinica Biotechnology Center in Southern Taiwan for the assistance with confocal microscopy. We also thank High Q Foundation (USA) for providing pHttQP25-GFP, pHttQP72-GFP, and pHttQP103-GFP expression vectors and Dr. Roger Y. Tsien (University of San Diego, USA) for pCDNA3.1-mCherry vector. This work was supported by the National Science Council grants (NSC 101-2311-B-006-006, NSC 100-2311-B-006-002, NSC 99-2311-B-006-001 and NSC 102-2311-B-006-004); the Ministry of Science and Technology grants (103-2320-B-006-040 and 104-2320-B-006-013); and in part, the Ministry of Education grant (The Aim for the Top University Project to the National Cheng Kung University), Taiwan, R.O.C. The authors declare that they have no conflict of interest.
Funding Information:
Funding This work was supported by the National Science Council grants (NSC 101-2311-B-006-006, NSC 100-2311-B-006-002, NSC 99-2311-B-006-001 and NSC 102-2311-B-006-004); the Ministry of Science and Technology grants (103-2320-B-006-040 and 104-2320-B-006-013); and in part, the Ministry of Education grant (The Aim for the Top University Project to the National Cheng Kung University), Taiwan, R.O.C.
Publisher Copyright:
© 2016, Springer Science+Business Media New York.
PY - 2017/11/1
Y1 - 2017/11/1
N2 - 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.
AB - 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.
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U2 - 10.1007/s12035-016-0247-y
DO - 10.1007/s12035-016-0247-y
M3 - Article
C2 - 27815841
AN - SCOPUS:84994383118
VL - 54
SP - 7382
EP - 7400
JO - Molecular Neurobiology
JF - Molecular Neurobiology
SN - 0893-7648
IS - 9
ER -