Quality control of inner nuclear membrane proteins by the Asi complex

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Science  07 Nov 2014:
Vol. 346, Issue 6210, pp. 751-755
DOI: 10.1126/science.1255638

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Trashing misfolded membrane proteins

Proteins move to and from the inner nuclear membrane (INM) from the rest of the endoplasmic reticulum through the nuclear pores. This movement is tightly controlled. Consequently, the INM accumulates a specific set of proteins required for a variety of functions, including chromosome organization and transcriptional control. But when INM proteins misfold, how are they eliminated? Foresti et al. addressed this question in yeast and found that a previously elusive branch of the endo–plasmic reticulum–associated degradation system was key (see the Perspective by Shao and Hegde).

Science, this issue p. 751; see also p. 701


Misfolded proteins in the endoplasmic reticulum (ER) are eliminated by a quality control system called ER-associated protein degradation (ERAD). However, it is unknown how misfolded proteins in the inner nuclear membrane (INM), a specialized ER subdomain, are degraded. We used a quantitative proteomics approach to reveal an ERAD branch required for INM protein quality control in yeast. This branch involved the integral membrane proteins Asi1, Asi2, and Asi3, which assembled into an Asi complex. Besides INM misfolded proteins, the Asi complex promoted the degradation of functional regulators of sterol biosynthesis. Asi-mediated ERAD was required for ER homeostasis, which suggests that spatial segregation of protein quality control systems contributes to ER function.

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