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J. Biol. Chem., Vol. 283, Issue 30, 20914-20924, July 25, 2008

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Human XTP3-B Forms an Endoplasmic Reticulum Quality Control Scaffold with the HRD1-SEL1L Ubiquitin Ligase Complex and BiP^*

Nobuko Hosokawa¹, Ikuo Wada^¶, Koji Nagasawa, Tatsuya Moriyama^||, Katsuya Okawa^**, and Kazuhiro Nagata

From the Department of Molecular and Cellular Biology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8397, Japan, the ^¶Department of Cell Sciences, Institute of Biomedical Sciences, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan Core Research for Evolutional Sciences and Technology, Japan Science and Technology Agency, Saitama 332-0012, Japan, the ^||Department of Applied Cell Biology, Graduate School of Agriculture, Kinki University, Nara 631-8505, Japan, and the ^**Frontier Technology Center, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan

The recognition of terminally misfolded proteins in the endoplasmic reticulum (ER) and the extraction of these proteins to the cytoplasm for proteasomal degradation are determined by a quality control mechanism in the ER. In yeast, Yos9p, an ER lectin containing a mannose 6-phosphate receptor homology (MRH) domain, enhances ER-associated degradation (ERAD) of glycoproteins. We show here that human XTP3-B (hXTP3-B), an ER lectin containing two MRH domains, has two transcriptional variants, and both isoforms retard ERAD of the human ₁-antitrypsin variant null Hong Kong (NHK), a terminally misfolded glycoprotein. The hXTP3-B long isoform strongly inhibited ERAD of NHK-QQQ, which lacks all of the N-glycosylation sites of NHK, but the short transcriptional variant of hXTP3-B had almost no effect. Examination of complex formation by immunoprecipitation and by fractionation using sucrose density gradient centrifugation revealed that the hXTP3-B long isoform associates with the HRD1-SEL1L membrane-anchored ubiquitin ligase complex and BiP, forming a 27 S ER quality control scaffold complex. The hXTP3-B short isoform, however, is excluded from scaffold formation. Another MRH domain-containing ER lectin, hOS-9, is incorporated into this large complex, but gp78, another mammalian homolog of the yeast ubiquitin ligase Hrd1p, is not. Based on these results, we propose that this large ER quality control scaffold complex, containing ER lectins, a chaperone, and a ubiquitin ligase, provides a platform for the recognition and sorting of misfolded glycoproteins as well as nonglycosylated proteins prior to retrotranslocation into the cytoplasm for degradation.

Received for publication, November 14, 2007 , and in revised form, April 21, 2008.

^* Parts of this work were supported by grants from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (to N. H., I. W., and K. N.) and the Uehara Memorial Foundation (to N. H.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1–4.

¹ To whom correspondence should be addressed: Dept. of Molecular and Cellular Biology, Institute for Frontier Medical Sciences, Kyoto University, 53 Kawahara-cho, Sakyo-ku, Kyoto 606-8397, Japan. E-mail: nobuko{at}frontier.kyoto-u.ac.jp.

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