Function of inhibitor of Bruton's tyrosine kinase isoform α(IBTKα) in nonalcoholic steatohepatitis links autophagy and the unfolded protein response

Jeffrey A. Willy, Sara K. Young, Amber Mosley, Samer Gawrieh, James L. Stevens, Howard Masuoka, Ronald Wek

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Nonalcoholic fatty liver disease (steatosis) is the most prevalent iver disease in the Western world. One of the advanced pathologies is nonalcoholic steatohepatitis (NASH), which is associated with induction of the unfolded protein response (UPR) and disruption of autophagic flux. However, the mechanisms by which these processes contribute to the pathogenesis of human diseases are unclear. Herein, we identify theα isoform of the inhibitor of Bruton's tyrosine kinase (IBTKα) as a member of the UPR, whose expression is preferentially translated during endoplasmic reticulum (ER) stress. We found that IBTKα is located in the ER and associates with proteins LC3b, SEC16A, and SEC31A and plays a previously unrecognized role in phagophore initiation from ER exit sites. Depletion of IBTKα helps prevent accumulation of autophagosome intermediates stemming from exposure to saturated free fatty acids and rescues hepatocytes from death. Of note, induction of IBTKα and the UPR, along with inhibition of autophagic flux, was associated with progression from steatosis to NASH in liver biopsies. These results indicate a function for IBTKα in NASH that links autophagy with activation of the UPR.

Original languageEnglish (US)
Pages (from-to)14050-14065
Number of pages16
JournalJournal of Biological Chemistry
Volume292
Issue number34
DOIs
StatePublished - Aug 25 2017

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Unfolded Protein Response
Autophagy
Protein Isoforms
Proteins
Endoplasmic Reticulum
Liver
Fluxes
Western World
Endoplasmic Reticulum Stress
Biopsy
Pathology
Fatty Liver
Nonesterified Fatty Acids
Hepatocytes
Fatty Acids
Chemical activation
Agammaglobulinaemia tyrosine kinase
Non-alcoholic Fatty Liver Disease

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

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title = "Function of inhibitor of Bruton's tyrosine kinase isoform α(IBTKα) in nonalcoholic steatohepatitis links autophagy and the unfolded protein response",
abstract = "Nonalcoholic fatty liver disease (steatosis) is the most prevalent iver disease in the Western world. One of the advanced pathologies is nonalcoholic steatohepatitis (NASH), which is associated with induction of the unfolded protein response (UPR) and disruption of autophagic flux. However, the mechanisms by which these processes contribute to the pathogenesis of human diseases are unclear. Herein, we identify theα isoform of the inhibitor of Bruton's tyrosine kinase (IBTKα) as a member of the UPR, whose expression is preferentially translated during endoplasmic reticulum (ER) stress. We found that IBTKα is located in the ER and associates with proteins LC3b, SEC16A, and SEC31A and plays a previously unrecognized role in phagophore initiation from ER exit sites. Depletion of IBTKα helps prevent accumulation of autophagosome intermediates stemming from exposure to saturated free fatty acids and rescues hepatocytes from death. Of note, induction of IBTKα and the UPR, along with inhibition of autophagic flux, was associated with progression from steatosis to NASH in liver biopsies. These results indicate a function for IBTKα in NASH that links autophagy with activation of the UPR.",
author = "Willy, {Jeffrey A.} and Young, {Sara K.} and Amber Mosley and Samer Gawrieh and Stevens, {James L.} and Howard Masuoka and Ronald Wek",
year = "2017",
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T1 - Function of inhibitor of Bruton's tyrosine kinase isoform α(IBTKα) in nonalcoholic steatohepatitis links autophagy and the unfolded protein response

AU - Willy, Jeffrey A.

AU - Young, Sara K.

AU - Mosley, Amber

AU - Gawrieh, Samer

AU - Stevens, James L.

AU - Masuoka, Howard

AU - Wek, Ronald

PY - 2017/8/25

Y1 - 2017/8/25

N2 - Nonalcoholic fatty liver disease (steatosis) is the most prevalent iver disease in the Western world. One of the advanced pathologies is nonalcoholic steatohepatitis (NASH), which is associated with induction of the unfolded protein response (UPR) and disruption of autophagic flux. However, the mechanisms by which these processes contribute to the pathogenesis of human diseases are unclear. Herein, we identify theα isoform of the inhibitor of Bruton's tyrosine kinase (IBTKα) as a member of the UPR, whose expression is preferentially translated during endoplasmic reticulum (ER) stress. We found that IBTKα is located in the ER and associates with proteins LC3b, SEC16A, and SEC31A and plays a previously unrecognized role in phagophore initiation from ER exit sites. Depletion of IBTKα helps prevent accumulation of autophagosome intermediates stemming from exposure to saturated free fatty acids and rescues hepatocytes from death. Of note, induction of IBTKα and the UPR, along with inhibition of autophagic flux, was associated with progression from steatosis to NASH in liver biopsies. These results indicate a function for IBTKα in NASH that links autophagy with activation of the UPR.

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