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The role of ubiquitin-conjugating enzyme Ube2j1 phosphorylation and its degradation by proteasome during endoplasmic stress recovery.

ABSTRACT: The human Ube2j1 and Ube2j2 are the only ubiquitin-conjugating enzymes (E2s) that are localized to endoplasmic reticulum (ER) through its C-terminal transmembrane domains. Ube2j1 is a known substrate of MAPK signalling pathway and it is phosphorylated at serine-184 during ER stress. Here, we demonstrate that Ube2j1, not Ube2j2 is essential for the recovery of cells from transient ER stress. The ectopic expression of wild-type Ube2j1 and phospho-mimic mutant, Ube2j1^S184D but not phospho-mutant Ube2j1^S184A can recover cells from ER stress. We also found that ubiquitin-ligase (E3), c-IAP1 preferentially interacts with phosphorylated Ube2j1. Moreover, we noticed that phosphorylated Ube2j1 is rapidly degraded by the proteasome during ER stress cell recovery. Taken together, these data suggest that Ube2j1 and its phosphorylation is important for transient ER stress cell recovery and the phosphorylated Ube2j1 is degraded by the proteasome.

SUBMITTER: Elangovan M

PROVIDER: S-EPMC5559397 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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The role of ubiquitin-conjugating enzyme Ube2j1 phosphorylation and its degradation by proteasome during endoplasmic stress recovery.

Elangovan Muthukumar M Chong Hae Kwan HK Park Jin Hee JH Yeo Eui Ju EJ Yoo Yung Joon YJ

Journal of cell communication and signaling 20170320 3

The human Ube2j1 and Ube2j2 are the only ubiquitin-conjugating enzymes (E2s) that are localized to endoplasmic reticulum (ER) through its C-terminal transmembrane domains. Ube2j1 is a known substrate of MAPK signalling pathway and it is phosphorylated at serine-184 during ER stress. Here, we demonstrate that Ube2j1, not Ube2j2 is essential for the recovery of cells from transient ER stress. The ectopic expression of wild-type Ube2j1 and phospho-mimic mutant, Ube2j1<sup>S184D</sup> but not phosph ...[more]

PMID: 28321712

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Project description:The Androgen Receptor (AR) is a pivotal protein in human physiology, exerting significant influence on both male and female physiology (PMID: 18434134, 25905231). Functioning as a nuclear transcription factor, AR binds to testosterone, translocates to the nucleus, and subsequently regulates the expression of numerous genes, impacting vital cellular processes such as cell proliferation, differentiation, and apoptosis (PMID: 4810760, 25237629). The prominent role of AR in human physiology is particularly notable in the context of prostate cancer initiation, where aberrant AR signaling has been identified as a key driver in tumorigenesis (PMID: 4810760, 27057074, 37429011). However, despite the considerable success of the current anti-androgen therapeutic approach, it faces the formidable challenge of drug resistance, significantly limiting the clinical outcome for patients and necessitating the urgent development of new therapeutic approaches to overcome resistance (PMID: 26563462, 24881730, 31363002, 35582713). Notably, one key feature of antiandrogen resistance is the sustained or enhanced AR signaling observed in many resistant tumors (PMID: 26563462, 34449248, 23580326), although the underlying molecular mechanisms remain largely unclear. Protein degradation, with ubiquitination at its core, plays a critical role in cell functionality, ensuring the elimination of redundant and harmful proteins (PMID: 16738015, 33634825). This intricate process involves the attachment of small proteins called ubiquitin to target proteins, marking them for degradation. Dysregulation of ubiquitination can lead to the accumulation of oncogenic proteins, contributing to tumorigenesis and therapy resistance in various cancers (PMID: 32296023, 33004065). The degradation of proteins is a complex process that involves the coordination of E1, E2 and E3 enzymes, with E3 enzymes binding to the target protein (PMID: 21111229, 20930542). Logically, research has focused on finding E3s targeting AR for degradation but has overlooked the role that E2s play in the ubiquitination process. In recent years, E2s have been shown to dictate the how and where ubiquitin gets attached in the target protein, dictating the fate of the protein (PMID: 27002219, 19851334). Therefore, finding the E2 involved in the degradation of AR can prove to be essential. In this study, we conducted an in vivo library screening approach and identified UBE2J1 as the bona fide E2 ubiquitin conjugating enzyme for AR ubiquitination. Our results demonstrated that the frequent loss of UBE2J1 in prostate cancer leads to dysregulated and impaired AR ubiquitination and degradation. Consequently, this promotes the accumulation of AR proteins and confers resistance to antiandrogen treatment in UBE2J1-deficient prostate cancer cells. To address this, we developed an innovative ubiquitination-based AR degrader that effectively restores AR ubiquitination, thereby resensitizing prostate cancer cells to antiandrogen therapy. These findings not only unveil the pivotal role of UBE2J1 as the crucial E2 ubiquitin conjugating enzyme for AR degradation but also shed light on a novel mechanism through which advanced prostate cancer cells upregulate AR protein levels, thereby acquiring resistance to existing antiandrogen therapy. These novel insights hold the potential to inform the development of more effective therapeutic strategies against advanced prostate cancers.

Dataset Information

The role of ubiquitin-conjugating enzyme Ube2j1 phosphorylation and its degradation by proteasome during endoplasmic stress recovery.

Publications

The role of ubiquitin-conjugating enzyme Ube2j1 phosphorylation and its degradation by proteasome during endoplasmic stress recovery.

Similar Datasets

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