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Endoplasmic reticulum lectin XTP 3‐B inhibits endoplasmic reticulum‐associated degradation of a misfolded α1‐antitrypsin variant
Author(s) -
Fujimori Tsutomu,
Kamiya Yukiko,
Nagata Kazuhiro,
Kato Koichi,
Hosokawa Nobuko
Publication year - 2013
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.12157
Subject(s) - endoplasmic reticulum associated protein degradation , endoplasmic reticulum , microbiology and biotechnology , glycoprotein , lysosome , glycan , ubiquitin , biochemistry , chemistry , ubiquitin ligase , secretory pathway , lectin , biology , golgi apparatus , enzyme , unfolded protein response , gene
The endoplasmic reticulum ( ER ) is an organelle that synthesizes many secretory and membrane proteins. However, proteins often fold incorrectly. Terminally misfolded polypeptides in the ER are retro‐translocated to the cytosol, where they are ultimately degraded by the ubiquitin–proteasome system, a process termed ER ‐associated degradation ( ERAD ). By recognizing the specific structures of N‐linked oligosaccharides attached to polypeptides, lectins play an important role in the quality control of glycoproteins in the ER . Mammalian OS ‐9 and XTP 3‐B are ER ‐resident lectins that contain mannose 6‐phosphate receptor homology ( MRH ) domains, which recognize sugar moieties; OS ‐9 has one MRH domain and XTP 3‐B has two. Both are involved in ERAD , but the functional differences between the two are poorly understood. The present study analyzed the function of human XTP 3‐B, and found, by frontal affinity chromatography analysis, that its C‐terminal MRH domain specifically recognized the Man 9 Glc NA c 2 (M9) glycan in vitro and M9 glycans on an ERAD substrate NHK , a terminally misfolded α1‐antitrypsin variant, in vivo . Furthermore, endogenous XTP 3‐B was a component of the HRD 1– SEL 1L membrane‐embedded ubiquitin ligase complex, an association that was stabilized by a direct interaction with SEL 1L. The lectin activity of XTP 3‐B was required for its binding to NHK , but not for its association with SEL 1L. Unlike OS ‐9, XTP 3‐B did not enhance the degradation of misfolded glycoproteins, but instead inhibited the degradation of NHK bearing M9 oligosaccharides. Therefore, we propose that XTP 3‐B recognizes M9 glycans on unfolded polypeptides, thereby acting as a negative regulator of ERAD , and also protects newly synthesized immature polypeptides from premature degradation.