Endoplasmic reticulum-associated protein degradation—one model fits all?

ABSTRACT Human immunodeficiency virus type 1 (HIV-1) is dependent on its envelope glycoprotein (Env) to bind, fuse, and subsequently infect a cell. We show here that treatment of HIV-1-infected cells with glycyl-prolyl-glycine amide (GPG-NH2), dramatically reduced the infectivity of the released viral particles by decreasing their Env incorporation. The mechanism of GPG-NH2 was uncovered by examining Env expression and maturation in treated cells. GPG-NH2 treatment was found to affect Env by significantly decreasing its steady-state levels, its processing into gp120/gp41, and its mass by inducing glycan removal in a manner dependent on its native signal sequence and the proteasome. Therefore, GPG-NH2 negatively impacts Env maturation, facilitating its targeting for endoplasmic reticulum-associated protein degradation, where Env is deglycosylated en route to its degradation. These findings illustrate that nontoxic drugs such as GPG-NH2, which can selectively target glycoproteins to existing cellular degradation pathways, may be useful for pathogen therapy.

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Endoplasmic reticulum-associated protein degradation

International Review of Cytology ◽

10.1016/s0074-7696(05)23002-4 ◽

2002 ◽

pp. 39-81 ◽

Cited By ~ 50

Author(s):

Ernst Jarosch ◽

Uwe Lenk ◽

Thomas Sommer

Keyword(s):

Endoplasmic Reticulum ◽

Protein Degradation

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A SEL1L Mutation Links a Canine Progressive Early-Onset Cerebellar Ataxia to the Endoplasmic Reticulum–Associated Protein Degradation (ERAD) Machinery

PLoS Genetics ◽

10.1371/journal.pgen.1002759 ◽

2012 ◽

Vol 8 (6) ◽

pp. e1002759 ◽

Cited By ~ 37

Author(s):

Kaisa Kyöstilä ◽

Sigitas Cizinauskas ◽

Eija H. Seppälä ◽

Esko Suhonen ◽

Janis Jeserevics ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Protein Degradation ◽

Cerebellar Ataxia ◽

Early Onset

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N-terminal acetylation of the yeast Derlin Der1 is essential for Hrd1 ubiquitin-ligase activity toward luminal ER substrates

Molecular Biology of the Cell ◽

10.1091/mbc.e12-11-0838 ◽

2013 ◽

Vol 24 (7) ◽

pp. 890-900 ◽

Cited By ~ 31

Author(s):

Dimitrios Zattas ◽

David J. Adle ◽

Eric M. Rubenstein ◽

Mark Hochstrasser

Keyword(s):

Endoplasmic Reticulum ◽

Transcription Factor ◽

Fusion Protein ◽

Protein Degradation ◽

Ubiquitin Ligase ◽

Ubiquitin Ligases ◽

Recent Analysis ◽

Specific Class ◽

Wild Type ◽

Ubiquitin Ligase Activity

Two conserved ubiquitin ligases, Hrd1 and Doa10, mediate most endoplasmic reticulum–associated protein degradation (ERAD) in yeast. Degradation signals (degrons) recognized by these ubiquitin ligases remain poorly characterized. Doa10 recognizes the Deg1 degron from the MATα2 transcription factor. We previously found that deletion of the gene (NAT3) encoding the catalytic subunit of the NatB N-terminal acetyltransferase weakly stabilized a Deg1-fusion protein. By contrast, a recent analysis of several MATα2 derivatives suggested that N-terminal acetylation of these proteins by NatB was crucial for recognition by Doa10. We now analyze endogenous MATα2 degradation in cells lacking NatB and observe minimal perturbation relative to wild-type cells. However, NatB mutation strongly impairs degradation of ER-luminal Hrd1 substrates. This unexpected defect derives from a failure of Der1, a Hrd1 complex subunit, to be N-terminally acetylated in NatB mutant yeast. We retargeted Der1 to another acetyltransferase to show that it is the only ERAD factor requiring N-terminal acetylation. Preventing Der1 acetylation stimulates its proteolysis via the Hrd1 pathway, at least partially accounting for the ERAD defect observed in the absence of NatB. These results reveal an important role for N-terminal acetylation in controlling Hrd1 ligase activity toward a specific class of ERAD substrates.

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