The Ubiquitin Receptor ADRM1 Modulates HAP40-Induced Proteasome Activity

Abstract

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.

Single Live Cell Monitoring of Protein Turnover Reveals Intercellular Variability and Cell-Cycle Dependence of Degradation Rates

“…Finally, we asked whether differences in proteasome activity could account for intercellular variability in protein degradation rates. While the rate-limiting components of protein degradation are not known, raising the levels of ADRM1, which acts as a ubiquitin receptor and is part of the 19S subunit of the proteasome, was reported to increase proteasome activity (Huang and Her, 2017). We thus asked whether the expression levels of ADRM1 (E) Example of correlation between degradation and synthesis rates for the SEP15 protein on n = 30 single cell traces.…”

Adhesion Regulating Molecule 1 Mediates HAP40 Overexpression-Induced Mitochondrial Defects

“…HAP40 is a novel protein whose level is associated with HD patients and HD model systems 20 . Our previous study has shown that overexpression of HAP40 is able to aggravate accumulation of mutant Htt aggregates 24 . Here, we report that overexpression of HAP40 results in mitochondrial fragmentation and causes defective mitochondrial functions.…”

“…1) Overexpression of ADRM1 is able to reduce phosphorylated Drp1 Ser616 protein level and relieves HAP40 overexpression-induced mitochondrial defects (Figure 6 and 7 ), and 2) reducing Drp1 activity through Mdivi-1 treatment is sufficient to alleviate multiple mitochondrial defects in striatal cells overexpressing HAP40 (Figure 8 ). Moreover, reducing Drp1 activity is equally sufficient to alleviate multiple mitochondrial defects caused by reduction of ADRM1 (Figure 9 ), which is negatively regulated by HAP40 24 . Taken together, our results provide compelling evidence to elucidate the HAP40-ADRM1-Drp1 pathway in regulating mitochondrial functions.…”

“…However, the molecular mechanism leading to the HD-associated mitochondrial defects is unclear. Our previous studies have shown that overexpression of HAP40 impairs proteasome activity and increases accumulation of mutant Htt in the striatal HD model cells 24 . Interestingly, the level of ADRM1, an ubiquitin receptor, is reduced after HAP40 overexpression.…”

The Effect of Dysfunctional Ubiquitin Enzymes in the Pathogenesis of Most Common Diseases

“…Huntingtin-associated protein (HAP40) is another protein affecting the proteasomal activity in HD. The overexpression of this protein stimulates mutant Htt aggregation due to the impaired UPS [152]. An in vivo study demonstrated that intraneuronal Huntington filaments but not inclusion bodies inhibit proteasome activity [153].…”