iRhom1 regulates proteasome activity via PAC1/2 under ER stress

Abstract

Proteasome is a protein degradation complex that plays a major role in maintaining cellular homeostasis. Despite extensive efforts to identify protein substrates that are degraded through ubiquitination, the regulation of proteasome activity itself under diverse signals is poorly understood. In this study, we have isolated iRhom1 as a stimulator of proteasome activity from genome-wide functional screening using cDNA expression and an unstable GFP-degron. Downregulation of iRhom1 reduced enzymatic activity of proteasome complexes and overexpression of iRhom1 enhanced it. Native-gel and fractionation analyses revealed that knockdown of iRhom1 expression impaired the assembly of the proteasome complexes. The expression of iRhom1 was increased by endoplasmic reticulum (ER) stressors, such as thapsigargin and tunicamycin, leading to the enhancement of proteasome activity, especially in ER-containing microsomes. iRhom1 interacted with the 20S proteasome assembly chaperones PAC1 and PAC2, affecting their protein stability. Moreover, knockdown of iRhom1 expression impaired the dimerization of PAC1 and PAC2 under ER stress. In addition, iRhom1 deficiency in D. melanogaster accelerated the rough-eye phenotype of mutant Huntingtin, while transgenic flies expressing either human iRhom1 or Drosophila iRhom showed rescue of the rough-eye phenotype. Together, these results identify a novel regulator of proteasome activity, iRhom1, which functions via PAC1/2 under ER stress.

TOM1 Regulates Neuronal Accumulation of Amyloid-β Oligomers by FcγRIIb2 Variant in Alzheimer's Disease

“…9C,D). It was previously reported that miR-126 targets 3Ј-UTR of TOM1 mRNA to regulate its expression and may be involved in several neuropsychiatric disorders (Oglesby et al, 2010;Sonntag et al, 2012; and that miR-126 expression potentiates A␤ toxicity (Kim et al, 2016). Thus, we attempted to identify whether miR-126 regulated TOM1 level in AD model.…”

“…The cell-based functional screening was performed on the basis of the previous study (Lee et al, 2015). In the primary screening, HT22 cells were cotransfected with pEGFP-N1 and each of 120 cDNAs encoding endo-lysosomal proteins for 24 h and treated with 5 M oA␤ 1-42 for 36 h. Cells with apoptotic blebbing or shrunk morphology were regarded as dead cells.…”

Human rhomboid family-1 modulates clathrin coated vesicle-dependent pro-transforming growth factor α membrane trafficking to promote breast cancer progression

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Inactive rhomboid proteins: New mechanisms with implications in health and disease

“…Notably, a genome wide screen identified iRhom1 as a stimulator of proteasome activity [31] and iRhom1 has been implicated in regulation of the hypoxic transcription factor Hif1 [32]. Notably, mice null for Hif1 exhibit vascular defects, as do ADAM17 KO mice [26].…”