Chen M, Gutierrez GJ, Ronai ZA.. Ubiquitin-recognition protein Ufd1 couples the endoplasmic reticulum (ER) stress response to cell cycle control. Proc Natl Acad Sci USA 108: 9119-9124
The ubiquitin-recognition protein Ufd1 facilitates clearance of misfolded proteins through the endoplasmic reticulum (ER)-associated degradation (ERAD) pathway. Here we report that prolonged ER stress represses Ufd1 expression to trigger cell cycle delay, which contributes to ERAD. Remarkably, down-regulation of Ufd1 enhances ubiquitination and destabilization of Skp2 mediated by the anaphase-promoting complex or cyclosome bound to Cdh1 (APC/C(Cdh1)), resulting in accumulation of the cyclin-dependent kinase inhibitor p27 and a concomitant cell cycle delay during the G1 phase that enables more efficient clearance of misfolded proteins. Mechanistically, nuclear Ufd1 recruits the deubiquitinating enzyme USP13 to counteract APC/C(Cdh1)-mediated ubiquitination of Skp2. Our data identify a coordinated cell cycle response to prolonged ER stress through regulation of the Cdh1-Skp2-p27 axis by Ufd1 and USP13.
[Show abstract] [Hide abstract] ABSTRACT: This study aimed to investigate peripheral blood gene expression in ultra-high-risk subjects (UHR) compared to first-episode psychosis individuals (FEP) and healthy controls (HC). We enrolled 22 UHR, 66 FEP and 67 HC and investigated the expression of 12 genes using Taqman assays. We used the Univariate General Linear Model, as well as Bonferroni correction for multiple comparisons. We found that UFD1L (ubiquitin fusion degradation 1 like (yeast)) gene was upregulated in UHR group compared to HC and FEP (P = 3.44 × 10(-6) ; P = 9.41 × 10(-6)). MBP (myelin basic protein) was downregulated in UHR compared to FEP (P = 6.07 × 10(-6)). DISC1 (disrupted in schizophrenia 1) was also upregulated in UHR compared to FEP but lost statistical significance when corrected for age. These genes are directly related to neurodevelopmental processes and have been associated to schizophrenia. Recent findings described that DISC1 overexpression can disrupt MBP expression, thus, we think that these alterations in UHR individuals could be associated with a common process. UFD1L showed a different pattern of expression only for UHR group, suggesting that they can be under an acute endoplasmatic reticulum stress, demanding elevated levels of Ufd1. Further studies can improve knowledge on disease progression and putative targets to preventive strategies.
- "This p97-Ufd1-Npl4 complex acts in endoplasmatic reticulum (ER) associated degradation (ERAD), extracting misfolded proteins marked with ubiquitin from ER to be degraded in cytosol by the proteasome (Ye et al. 2001). Thus, it was suggested that Ufd1 is directly associated with stress response in ERAD (Chen et al. 2011). UFD1L SNP, rs5992403, has been associated with schizophrenia (De Luca et al. 2001 ), with earlyonset of the disorder (Ota et al. 2010) and with a defi cit in the set-shifting task (which represents a defi cit in fundamental dimensions of cognition in schizophrenia) (Ota et al. 2013). "
[Show abstract] [Hide abstract] ABSTRACT: The process of cell death has important physiological implications. At the organism level it is mostly involved in maintenance of tissue homeostasis. At the cellular level, the strategies of cell death may be categorized as either suicide or sabotage. The mere fact that many of these processes are programmed and that these are often deregulated in pathological conditions is seed to thought. The various players that are involved in these pathways are highly regulated. One of the modes of regulation is via post-translational modifications such as ubiquitination and deubiquitination. In this review, we have first dealt with the different modes and pathways involved in cell death and then we have focused on the regulation of several proteins in these signaling cascades by the different deubiquitinating enzymes, in the perspective of cancer. The study of deubiquitinases is currently in a rather nascent stage with limited knowledge both in vitro and in vivo , but the emerging roles of the deubiquitinases in various processes and their specificity have implicated them as potential targets from the therapeutic point of view. This review throws light on another aspect of cancer therapeutics by targeting the deubiquitinating enzymes.
- "USP7 or HAUSP (herpesvirus-associated ubiquitin-specific protease) deubiquitinates SCF-í µí»½- TrCP mediated K48-linked Ub chains on claspin, the upstream regulator of Chk1 . USP13 counteracts S phase kinase-associated protein 2 (Skp2) ubiquitination via the anaphase promoting complex/cyclosome (APC/C Cdh1 ), delaying cell cycle by accumulation of p27  . USP19 deubiquitinates Kip1 ubiquitination-promoting complex protein 1 (KPC1) regulating p27 Kip1  and some KPC1 independent cell cycle regulation also exists . "
[Show abstract] [Hide abstract] ABSTRACT: Shadoo (Sho) is an N-glycosylated glycophosphatidylinositol-anchored protein that is expressed in the brain and exhibits neuroprotective properties. Recently, research has shown that a reduction of Sho levels may reflect the presence of PrP(Sc) in the brain. However, the possible mechanism by which prion infection triggers down-regulation of Sho remains unclear. In the present study, Western blot and immunohistochemical assays revealed that Sho, especially glycosylated Sho, declined markedly in the brains of five scrapie agent-infected hamsters and mice at the terminal stages. Analyses of the down-regulation of Sho levels with the emergence of PrP(Sc) C2 proteolytic fragments did not identify close association in all tested scrapie-infected models. To further investigate the mechanism of depletion of Sho in prion disease, a Sho-expressing plasmid with HA tag was introduced into a scrapie-infected cell line, SMB-S15, and its normal cell line, SMB-PS. Western blot assay revealed dramatically decreased Sho in SMB-S15 cells, especially its glycosylated form. Proteasome inhibitor MG132 reversed the decrease of nonglycosylated Sho, but had little effect on glycosylated Sho. N-acetylglucosamine transferase inhibitor tunicamycin efficiently reduced the glycosylations of Sho and PrP(C) in SMB-PS cells, while two other endoplasmic reticulum stress inducers showed clear inhibition of diglycosylated PrP(C), but did not change the expression level and profile of Sho. Furthermore, immunoprecipitation of HA-Sho illustrated ubiquitination of Sho in SMB-S15 cells, but not in SMB-PS cells. We propose that the depletions of Sho in scrapie-infected cell lines due to inhibition of glycosylation mediate protein destabilization and subsequently proteasome degradation after modification by ubiquitination.
- "Posttranslational N-glycosylation plays a crucial role in the ERQC system to strictly preserve proteostasis . The inhibition of N-glycosylation activates ER-specific stress responses in neurons , which include the ER-associated degradation (ERAD) mechanism responsible for differential and extremely efficient degradation of nonglycosylated protein by the proteasome after ubiquitination323334. Additionally, we do not observe the co-localization between Sho and PrP Sc both in the brains Author's personal copy of scrapie-infected animals and in the scrapie-infected cell line, which may indicate that it is not possible that downregulation of endogenous Sho is due to the direct interaction with exogenous prion agent. "