Abstract
The nuclear envelope consists of inner and outer nuclear membranes. Whereas the outer membrane is an extension of the endoplasmic reticulum, the inner nuclear membrane (INM) represents a unique membranous environment containing specific proteins. The mechanisms of integral INM protein degradation are unknown. Here, we investigated the turnover of Asi2, an integral INM protein in Saccharomyces cerevisiae. We report that Asi2 is degraded by the proteasome independently of the vacuole and that it exhibited a half-life of ∼45 min. Asi2 exhibits enhanced stability in mutants lacking the E2 ubiquitin conjugating enzymes Ubc6 or Ubc7, or the E3 ubiquitin ligase Doa10. Consistent with these data, Asi2 is post-translationally modified by poly-ubiquitylation in a Ubc7- and Doa10-dependent manner. Importantly Asi2 degradation is significantly reduced in a sts1-2 mutant that fails to accumulate proteasomes in the nucleus, indicating that Asi2 is degraded in the nucleus. Our results reveal a molecular pathway that affects the stability of integral proteins of the inner nuclear membrane and indicate that Asi2 is subject to protein quality control in the nucleus.
Highlights
The confinement of the genome within the nucleus by the nuclear envelope is a hallmark of eukaryotic cells
Asi2 exhibits turnover independently of SPS sensor signaling In order to characterize the degradation of the inner nuclear membrane (INM) protein Asi2, we first investigated the turnover rate of functional Asi2 proteins carrying N-terminal Myc or HA epitope tags (Zargari et al, 2007)
In this study, we addressed the molecular basis of INM protein turnover by examining the stability of Asi2, a well-characterized integral INM protein in yeast (Zargari et al, 2007)
Summary
The confinement of the genome within the nucleus by the nuclear envelope is a hallmark of eukaryotic cells. These include the diffusion and nuclear retention model, nuclear localization signal (NLS)mediated transport through peripheral channels of the NPC (reviewed in Zuleger et al, 2012) and, more recently, NLSmediated transport through the central NPC channel (Meinema et al, 2011). In contrast to their nuclear targeting, the fate of the integral membrane proteins once they have reached the INM is less clear. Whether integral INM proteins are subject to turnover, and if so, what degradative pathway is involved, remains an intriguing and unsolved biological question
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