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Proteomic characterization of endogenous substrates of mammalian ubiquitin ligase Hrd1

Overview of attention for article published in Cell & Bioscience, August 2018
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Title
Proteomic characterization of endogenous substrates of mammalian ubiquitin ligase Hrd1
Published in
Cell & Bioscience, August 2018
DOI 10.1186/s13578-018-0245-z
Pubmed ID
Authors

Yilin Ye, Suk-Hwan Baek, Yihong Ye, Ting Zhang

Abstract

Endoplasmic reticulum (ER)-associated degradation (ERAD) regulates protein homeostasis in the secretory pathway by targeting misfolded or unassembled proteins for degradation by the proteasome. Hrd1 is a conserved multi-spanning membrane bound ubiquitin ligase required for ubiquitination of many aberrant ER proteins, but few endogenous substrates of Hrd1 have been identified to date. Using a SILAC-based quantitative proteomic approach combined with CRISPR-mediated gene silencing, we searched for endogenous physiological substrates of Hrd1. We used RNA microarray, immunoblotting, cycloheximide chase combined with chemical genetics to define the role of Hrd1 in regulating the stability of endogenous ERAD substrates. We identified 58 proteins whose levels are consistently upregulated in Hrd1 null HEK293 cells. Many of these proteins function in pathways involved in stress adaptation or immune surveillance. We validated OS9, a lectin required for ERAD of glycoproteins as a highly upregulated protein in Hrd1 deficient cells. Moreover, the abundance of OS9 is inversely correlated with Hrd1 level in clinical synovium samples isolated from osteoarthritis and rheumatoid arthritis patients. Intriguingly, immunoblotting detects two OS9 variants, both of which are upregulated when Hrd1 is inactivated. However, only one of these variants is subject to proteasome dependent degradation that requires Hrd1 and the AAA (ATPase associated with diverse cellular activities) ATPase p97. The stability of the other variant on the other hand is influenced by a lysosomal inhibitor. Hrd1 regulates the stability of proteins involved in ER stress response and immune activation by both proteasome dependent and independent mechanisms.

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Mendeley readers

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The data shown below were compiled from readership statistics for 34 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Unknown 34 100%

Demographic breakdown

Readers by professional status Count As %
Researcher 8 24%
Student > Ph. D. Student 7 21%
Professor > Associate Professor 2 6%
Student > Bachelor 2 6%
Professor 1 3%
Other 2 6%
Unknown 12 35%
Readers by discipline Count As %
Biochemistry, Genetics and Molecular Biology 8 24%
Agricultural and Biological Sciences 6 18%
Medicine and Dentistry 3 9%
Immunology and Microbiology 2 6%
Chemistry 2 6%
Other 1 3%
Unknown 12 35%
Attention Score in Context

Attention Score in Context

This research output has an Altmetric Attention Score of 1. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 22 August 2018.
All research outputs
#18,647,094
of 23,100,534 outputs
Outputs from Cell & Bioscience
#584
of 955 outputs
Outputs of similar age
#256,694
of 334,082 outputs
Outputs of similar age from Cell & Bioscience
#6
of 11 outputs
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