Fujimori T, Kamiya Y, Nagata K, Kato K, Hosokawa N

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 ...

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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 XTP3-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 XTP3-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 XTP3-B and found that its C-terminal MRH domain specifically recognized the Man(9) GlcNAc(2) (M9) glycan by frontal affinity chromatography analysis in vitro and M9 glycans on an ERAD substrate NHK, a terminally misfolded α1-antitrypsin variant, in vivo. Furthermore, endogenous XTP3-B was a component of the HRD1-SEL1L membrane-embedded ubiquitin ligase complex, an association that was stabilized by a direct interaction with SEL1L. The lectin activity of XTP3-B was required for its binding to NHK, but not for its association with SEL1L. Unlike OS-9, XTP3-B did not enhance the degradation of misfolded glycoproteins, but instead inhibited the degradation of NHK bearing M9 oligosaccharides. Therefore, we propose that XTP3-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. © 2013 The Authors Journal compilation © 2013 FEBS.

Date: Jan. 29, 2013

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