Cdc48 and Ubx1 participate in a pathway associated with the inner nuclear membrane that governs Asi1 degradation

Pantazopoulou, Marina; Boban, Mirta; Foisner, Roland; Ljungdahl, Per O.

doi:10.1242/jcs.189332

Cited by 19 publications

(26 citation statements)

References 79 publications

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“…Our work therefore extends the role of APC/C in modulating the turnover of an integral membrane protein. It also enriches the repertoire of the ERAD pathway for protein quality control specifically at the INM, which is also termed INMAD for INM-associated protein degradation (Pantazopoulou et al, 2016). Accumulation of Mps3 leads to nuclear membrane expansion and impairs cell division (Friederichs et al, 2011;Li et al, 2017), thus demonstrating the significance of timely turnover of resident INM proteins, such as Mps3, at the nuclear envelope.…”

Section: Discussionmentioning

confidence: 99%

“…However, the Asi proteins, including Asi1, Asi2 and Asi3, are not conserved in mammals, and genome-wide proteomic analysis in budding yeast has shown that they are mostly responsible for the degradation of mislocalized INM proteins (Foresti et al, 2014;Khmelinskii et al, 2014). Noticeably, being a resident INM protein itself, Asi1 is highly unstable and subject to proteasome degradation, but the responsible E3 ligase for Asi1 turnover remains unknown (Pantazopoulou et al, 2016). These observations indicate that additional E3 ligases function at the INM to regulate protein turnover.…”

Section: Introductionmentioning

confidence: 99%

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The anaphase-promoting complex regulates the degradation of the inner nuclear membrane protein Mps3 in budding yeast

Koch¹,

Jin²,

Tomko³

et al. 2018

Preprint

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The nucleus is enclosed by the inner nuclear membrane (INM) and the outer nuclear membrane (ONM). While the ONM is continuous with the endoplasmic reticulum (ER), the INM is independent and separates the nucleoplasm from the ER lumen. To maintain INM homeostasis, proteins mislocalized to the INM are degraded by the ER-associated protein degradation (ERAD) pathway. However, the mechanism for turnover of resident INM proteins is less clear. Here we show that the anaphase-promoting complex/cyclosome (APC/C), an E3 ubiquitin ligase, regulates the degradation of Mps3, a conserved integral protein of the INM.Turnover of Mps3 requires the ubiquitin-conjugating enzymes Ubc7 and Ubc6, but not the three known ERAD ubiquitin ligases, Doa10, Hrd1, and the Asi1-Asi3 complex. Using a genetic approach, we have found that Cdh1, a coactivator of APC/C, modulates Mps3 stability. APC/C controls Mps3 degradation through Mps3's N-terminus, which resides in the nucleoplasm and possesses two putative APC/C-dependent destruction motifs. Accumulation of Mps3 at the INM impairs nuclear morphological changes and cell division. Our findings therefore reveal an unexpected mechanism of APC/C-mediated protein quality control at the INM that coordinates nuclear morphogenesis and cell-cycle progression.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The anaphase-promoting complex regulates the degradation of the inner nuclear membrane protein Mps3 in budding yeast

Koch¹,

Jin²,

Tomko³

et al. 2018

Preprint

View full text Add to dashboard Cite

show abstract

“…Additionally, recent studies have identified novel functions of the INM transmembrane Asi1-3 complex, and the soluble nuclear anaphase-promoting complex/cyclosome (APC/C) as E3 ligases working in conjunction with Ubc6 and Ubc7 to regulate protein turnover of substrates specifically at the INM (Figure 2; [31][32][33][34]). These spatially compartmentalized pathways have been termed INMAD for Inner Nuclear Membrane Associated Degradation [35]. Although initially designated as separate ERAD branches, for the purpose of this review both the Asi1-3 complex and Doa10 functioning at the INM will be referred to as INMAD ( Figure 2).…”

Section: Erad Degrades Er-associated Proteinsmentioning

confidence: 99%

Regulation of inner nuclear membrane associated protein degradation

Koch

2019

Nucleus

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The nucleus is enclosed by a double-membrane structure, the nuclear envelope, which separates the nucleoplasm from the cytoplasm. The outer nuclear membrane is continuous with the endoplasmic reticulum (ER), whereas the inner nuclear membrane (INM) is a specialized compartment with a unique proteome. In order to ensure compartmental homeostasis, INM-associated degradation (INMAD) is required for both protein quality control and regulated proteolysis of INM proteins. INMAD shares similarities with ER-associated degradation (ERAD). The mechanism of ERAD is well characterized, whereas the INMAD pathway requires further definition. Here we review the three different branches of INMAD, mediated by their respective E3 ubiquitin ligases: Doa10, Asi1-3, and APC/C. We clarify the distinction between ERAD and INMAD, their substrate recognition signals, and the subsequent processing by their respective degradation machineries. We also discuss the significance of cell-cycle and developmental regulation of protein clearance at the INM, and its relationship to human disease.

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“…Importantly, we also identified a decreased association between the mutant Cdc48 and the Ubxfamily member Shp1/Ubx1 at 48h. Shp1 is a known cofactor of Cdc48 associated with ERAD, nuclear membrane functions 42 , and autophagy 13 . Shp1 has been suggested as an antagonist of Ufd1, interacting with Cdc48 independently of the Ufd1-Npl4 complex and simultaneously with ubiquitylated substrates 5 .…”

Section: Mutation In Cys115 Alters Cdc48 Interactome Reflecting Diffmentioning

confidence: 99%

“…the Cdc48-Npl4-Vms1 complex mediates mitochondrialassociated degradation) 7 . Additional cofactors such as members of the Ubx-family are involved with Cdc48 in nuclear 19 and membrane lipid formation 20 pathways (Fig. 1B).…”

Section: Introductionmentioning

confidence: 99%

A molecular switch for Cdc48 activity and localization during oxidative stress and aging

Reichmann

Radzinski

Yogev

et al. 2019

Preprint

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Control over a healthy proteome begins with the birth of the polypeptide chain and ends with coordinated protein degradation. One of the major players in eukaryotic protein degradation is the essential and highly conserved ATPase, Cdc48 (p97/VCP in mammals). Cdc48 mediates clearance of misfolded proteins from the nucleus, cytosol, ER, mitochondria, and more. Here we dissect the crosstalk between cellular oxidation and Cdc48 activity by identification of a redox-sensitive site, Cys115. By integrating proteomics, biochemistry, microscopy, and bioinformatics, we show that removal of Cys115's redox-sensitive thiol group leads to accumulation of Cdc48 in the nucleus and consequently, results in severe defects in the oxidative stress response, mitochondrial fragmentation, and a decrease in ERAD and sterol biogenesis. We have thus identified a unique redox switch in Cdc48, which may provide a clearer picture of the importance of Cdc48's localization in maintaining a "healthy" proteome during oxidative stress and chronological aging in yeast.

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Cdc48 and Ubx1 participate in a pathway associated with the inner nuclear membrane that governs Asi1 degradation

Cited by 19 publications

References 79 publications

The anaphase-promoting complex regulates the degradation of the inner nuclear membrane protein Mps3 in budding yeast

The anaphase-promoting complex regulates the degradation of the inner nuclear membrane protein Mps3 in budding yeast

Regulation of inner nuclear membrane associated protein degradation

A molecular switch for Cdc48 activity and localization during oxidative stress and aging

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