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E3 ubiquitin ligase that recognizes sugar chains


N-glycosylation of proteins in the endoplasmic reticulum (ER) has a central role in protein quality control1,2,3. Here we report that N-glycan serves as a signal for degradation by the Skp1–Cullin1–Fbx2–Roc1 (SCFFbx2) ubiquitin ligase complex. The F-box protein Fbx2 (ref. 4) binds specifically to proteins attached to N-linked high-mannose oligosaccharides and subsequently contributes to ubiquitination of N-glycosylated proteins. Pre-integrin β1 is a target of Fbx2; these two proteins interact in the cytosol after inhibition of the proteasome. In addition, expression of the mutant Fbx2ΔF, which lacks the F-box domain that is essential for forming the SCF complex, appreciably blocks degradation of typical substrates of the ER-associated degradation pathway5,6. Our results indicate that SCFFbx2 ubiquitinates N-glycosylated proteins that are translocated from the ER to the cytosol by the quality control mechanism.

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Figure 1: The SCFFbx2 complex ubiquitinates N-glycosylated substrate in vitro.
Figure 2: Interaction of Fbx2 with endogenous high-mannose oligosaccharide-containing glycoproteins.
Figure 3: SCFFbx2 promotes proteasomal degradation of cytosolic glycoproteins.
Figure 4: Fbx2 functions in the ERAD pathway.


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We thank R. R. Kopito for the CFTRΔF508–GFP and HA–TCRα expression plasmids. This work was supported in part by grants from the program Grants-in-aid for Scientific Research from the Ministry of Education, Science, Sports, and Culture of Japan.

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Correspondence to Keiji Tanaka or Tadashi Tai.

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Yoshida, Y., Chiba, T., Tokunaga, F. et al. E3 ubiquitin ligase that recognizes sugar chains. Nature 418, 438–442 (2002).

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