Cytoplasmic destruction of p53 by the endoplasmic reticulum-resident ubiquitin ligase 'Synoviolin'

EMBO J. 2007 Jan 10;26(1):113-22. doi: 10.1038/sj.emboj.7601490.

Satoshi Yamasaki ¹, Naoko Yagishita, Takeshi Sasaki, Minako Nakazawa, Yukihiro Kato, Tadayuki Yamadera, Eunkyung Bae, Sayumi Toriyama, Rie Ikeda, Lei Zhang, Kazuko Fujitani, Eunkyung Yoo, Kaneyuki Tsuchimochi, Tomohiko Ohta, Natsumi Araya, Hidetoshi Fujita, Satoko Aratani, Katsumi Eguchi, Setsuro Komiya, Ikuro Maruyama, Nobuyo Higashi, Mitsuru Sato, Haruki Senoo, Takahiro Ochi, Shigeyuki Yokoyama, Tetsuya Amano, Jaeseob Kim, Steffen Gay, Akiyoshi Fukamizu, Kusuki Nishioka, Keiji Tanaka, Toshihiro Nakajima

Affiliations

Affiliation

1 Department of Genome Science, Institute of Medical Science, St Marianna University School of Medicine, Kawasaki, Japan.

PMID: 17170702 DOI: 10.1038/sj.emboj.7601490

Abstract

Synoviolin, also called HRD1, is an E3 ubiquitin Ligase and is implicated in endoplasmic reticulum -associated degradation. In mammals, Synoviolin plays crucial roles in various physiological and pathological processes, including embryogenesis and the pathogenesis of arthropathy. However, little is known about the molecular mechanisms of Synoviolin in these actions. To clarify these issues, we analyzed the profile of protein expression in synoviolin-null cells. Here, we report that Synoviolin targets tumor suppressor gene p53 for ubiquitination. Synoviolin sequestrated and metabolized p53 in the cytoplasm and negatively regulated its cellular level and biological functions, including transcription, cell cycle regulation and Apoptosis. Furthermore, these p53 regulatory functions of Synoviolin were irrelevant to Other E3 ubiquitin ligases for p53, such as MDM2, Pirh2 and Cop1, which form autoregulatory feedback loops. Our results provide novel insights into p53 signaling mediated by Synoviolin.

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