Mechanisms Underlying the Cellular Clearance of Antitrypsin Z: Lessons from Yeast Expression Systems

Gelling, Cristy; Brodsky, Jeffrey L.

doi:10.1513/pats.201001-007aw

Cited by 10 publications

(9 citation statements)

References 49 publications

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“…Presumably, the residual Ssa proteins in ssa1,2 and ssa2,3,4 mutants support the degradation of particular substrates although they are not sufficient to fully restore the rate of overall proteolysis. Interestingly, a mutant form of yeast membrane ATPase also showed a similar pattern of dependence on different Ssa proteins for its degradation [17]. The degradation of the “N-end rule” substrate arginine-β-galactosidase (R-gal) was also reduced in ssa1-45 ts mutant (Fig.…”

Section: Resultsmentioning

confidence: 95%

The requirements of yeast Hsp70 of SSA family for the ubiquitin-dependent degradation of short-lived and abnormal proteins

Lee

Sherman

Goldberg

2016

Biochemical and Biophysical Research Communications

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Cytoplasmic Hsp70s of SSA family, especially Ssa1p, are involved in the degradation of a variety of misfolded proteins in yeast. However the importance of other Ssa proteins in this process is unclear. To clarify the role(s) of individual Ssa proteins in proteolysis, we measured the breakdown of various cell proteins in mutants lacking different Ssa proteins. In mutants lacking Ssa1p and Ssa2p, the proteasomal degradation of short-lived proteins was reduced, which was not restored fully by the over-expression of Ssa1p. By contrast, the degradation of stable cellular proteins did not require Ssa proteins. The degradation of the cytosolic model substrates (Ub-P-β-gal and R-β-gal) and their ubiquitylation were inhibited by the inactivation of Ssa proteins. In addition, Ssa1p and the co-chaperone Ydj1p are indispensable for the intracellular degradation of a mutant secretory protein, Siiyama variant of human antitrypsin. Our findings indicate that both Ssa1p and Ssa2p are essential for the ubiquitin-dependent degradation of short-lived proteins and the requirements of Ssa proteins and the co-chaperones widely vary depending on the conformations and folding status of the substrates.

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Section: Resultsmentioning

confidence: 95%

The requirements of yeast Hsp70 of SSA family for the ubiquitin-dependent degradation of short-lived and abnormal proteins

Lee

Sherman

Goldberg

2016

Biochemical and Biophysical Research Communications

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“…Since then, AAT-Z and another mutant form of AAT, known as null Hong Kong (NHK), have been heavily utilized as model ERAD substrates, and much of what is now understood about the quality control of glycosylated proteins in the ER has been derived from the use of the NHK variant. It should also be noted that AAT-Z is a substrate that can be disposed of by multiple degradation pathways [132]. While AAT-Z was one of the model substrates to first demonstrate the existence of ERAD, it has also clearly been shown that AAT-Z enters the autophagy pathway and is degraded in the lysosome [133, 134].…”

Section: The Early History Of the Erad Pathwaymentioning

confidence: 99%

How early studies on secreted and membrane protein quality control gave rise to the ER associated degradation (ERAD) pathway: The early history of ERAD

Needham¹,

Brodsky²

2013

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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All newly synthesized proteins are subject to quality control check-points, which prevent aberrant polypeptides from harming the cell. For proteins that ultimately reside in the cytoplasm, components that also reside in the cytoplasm were known for many years to mediate quality control. Early biochemical and genetic data indicated that misfolded proteins were selected by molecular chaperones and then targeted to the proteasome (in eukaryotes) or to proteasome-like particles (in bacteria) for degradation. What was less clear was how secreted and integral membrane proteins, which in eukaryotes enter the endoplasmic reticulum (ER), were subject to quality control decisions. In this review, we highlight early studies that ultimately led to the discovery that secreted and integral membrane proteins also utilize several components that constitute the cytoplasmic quality machinery. This component of the cellular quality control pathway is known as ER associated degradation, or ERAD.

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“…Reports have suggested that accumulation of ZAAT polymers within the ER of hepatocytes activates proteasomal and autophagic degradation pathways [Perlmutter, 2006;Kroeger et al, 2009;Gelling and Brodsky, 2010;Ghouse et al, 2014]. Chaperones interacting with ZAAT in the ER include calnexin, protein-disulfide isomerase, GRP-78/BiP, EDEM1, and the N-glycan-modifying enzymes UDP-glucose: glycoprotein glucosyltransferase and a-mannosidase-like protein [Cabral et al, 2002;Schmidt and Perlmutter, 2005;Granell et al, 2008;Jang et al, 2015].…”

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confidence: 99%

Erdj3 Has an Essential Role for Z Variant Alpha‐1‐Antitrypsin Degradation

Khodayari

Marek

et al. 2017

J of Cellular Biochemistry

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Alpha‐1‐antitrypsin deficiency (AATD) is an inherited disease characterized by emphysema and liver disease. AATD is most often caused by a single amino acid substitution at amino acid 342 in the mature protein, resulting in the Z mutation of the alpha‐1‐antitrypsin gene (ZAAT). This substitution is associated with misfolding and accumulation of ZAAT in the endoplasmic reticulum (ER) of hepatocytes and monocytes, causing a toxic gain of function. Retained ZAAT is eliminated by ER‐associated degradation and autophagy. We hypothesized that alpha‐1‐antitrypsin (AAT)‐interacting proteins play critical roles in quality control of human AAT. Using co‐immunoprecipitation, we identified ERdj3, an ER‐resident Hsp40 family member, as a part of the AAT trafficking network. Depleting ERdj3 increased the rate of ZAAT degradation in hepatocytes by redirecting ZAAT to the ER calreticulin‐EDEM1 pathway, followed by autophagosome formation. In the Huh7.5 cell line, ZAAT ER clearance resulted from enhancing ERdj3‐mediated ZAAT degradation by silencing ERdj3 while simultaneously enhancing autophagy. In this context, ERdj3 suppression may eliminate the toxic gain of function associated with polymerization of ZAAT, thus providing a potential new therapeutic approach to the treatment of AATD‐related liver disease. J. Cell. Biochem. 118: 3090–3101, 2017. © 2017 The Authors. Journal of Cellular Biochemistry Published by Wiley Periodicals Inc.

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Mechanisms Underlying the Cellular Clearance of Antitrypsin Z: Lessons from Yeast Expression Systems

Cited by 10 publications

References 49 publications

The requirements of yeast Hsp70 of SSA family for the ubiquitin-dependent degradation of short-lived and abnormal proteins

The requirements of yeast Hsp70 of SSA family for the ubiquitin-dependent degradation of short-lived and abnormal proteins

How early studies on secreted and membrane protein quality control gave rise to the ER associated degradation (ERAD) pathway: The early history of ERAD

Erdj3 Has an Essential Role for Z Variant Alpha‐1‐Antitrypsin Degradation

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