A disease- and phosphorylation-related nonmechanical function for keratin 8

Nam-on Ku, M. Bishr Omary

Research output: Contribution to journalArticle

118 Citations (Scopus)

Abstract

Keratin 8 (K8) variants predispose to human liver injury via poorly understood mechanisms. We generated transgenic mice that overexpress the human disease-associated K8 Gly61-to-Cys (G61C) variant and showed that G61C predisposes to liver injury and apoptosis and dramatically inhibits K8 phosphorylation at serine 73 (S73) via stress-activated kinases. This led us to generate mice that overexpress K8 S73-to-Ala (S73A), which mimicked the susceptibility of K8 G61C mice to injury, thereby providing a molecular link between K8 phosphorylation and disease-associated mutation. Upon apoptotic stimulation, G61C and S73A hepatocytes have persistent and increased nonkeratin proapoptotic substrate phosphorylation by stress-activated kinases, compared with wild-type hepatocytes, in association with an inability to phosphorylate K8 S73. Our findings provide the first direct link between patient-related human keratin variants and liver disease predisposition. The highly abundant cytoskeletal protein K8, and possibly other keratins with the conserved S73-containing phosphoepitope, can protect tissue from injury by serving as a phosphate "sponge" for stress-activated kinases and thereby provide a novel nonmechanical function for intermediate filament proteins.

Original languageEnglish
Pages (from-to)115-125
Number of pages11
JournalJournal of Cell Biology
Volume174
Issue number1
DOIs
Publication statusPublished - 2006 Jul 3

Fingerprint

Keratin-8
Phosphorylation
Serine
Phosphotransferases
Wounds and Injuries
Keratins
Hepatocytes
Intermediate Filament Proteins
Cytoskeletal Proteins
Liver
Porifera
Transgenic Mice
Liver Diseases
Phosphates
Apoptosis
Mutation

All Science Journal Classification (ASJC) codes

  • Cell Biology

Cite this

@article{0e6a65b99954437fbc9c0880b53558c3,
title = "A disease- and phosphorylation-related nonmechanical function for keratin 8",
abstract = "Keratin 8 (K8) variants predispose to human liver injury via poorly understood mechanisms. We generated transgenic mice that overexpress the human disease-associated K8 Gly61-to-Cys (G61C) variant and showed that G61C predisposes to liver injury and apoptosis and dramatically inhibits K8 phosphorylation at serine 73 (S73) via stress-activated kinases. This led us to generate mice that overexpress K8 S73-to-Ala (S73A), which mimicked the susceptibility of K8 G61C mice to injury, thereby providing a molecular link between K8 phosphorylation and disease-associated mutation. Upon apoptotic stimulation, G61C and S73A hepatocytes have persistent and increased nonkeratin proapoptotic substrate phosphorylation by stress-activated kinases, compared with wild-type hepatocytes, in association with an inability to phosphorylate K8 S73. Our findings provide the first direct link between patient-related human keratin variants and liver disease predisposition. The highly abundant cytoskeletal protein K8, and possibly other keratins with the conserved S73-containing phosphoepitope, can protect tissue from injury by serving as a phosphate {"}sponge{"} for stress-activated kinases and thereby provide a novel nonmechanical function for intermediate filament proteins.",
author = "Nam-on Ku and Omary, {M. Bishr}",
year = "2006",
month = "7",
day = "3",
doi = "10.1083/jcb.200602146",
language = "English",
volume = "174",
pages = "115--125",
journal = "Journal of Cell Biology",
issn = "0021-9525",
publisher = "Rockefeller University Press",
number = "1",

}

A disease- and phosphorylation-related nonmechanical function for keratin 8. / Ku, Nam-on; Omary, M. Bishr.

In: Journal of Cell Biology, Vol. 174, No. 1, 03.07.2006, p. 115-125.

Research output: Contribution to journalArticle

TY - JOUR

T1 - A disease- and phosphorylation-related nonmechanical function for keratin 8

AU - Ku, Nam-on

AU - Omary, M. Bishr

PY - 2006/7/3

Y1 - 2006/7/3

N2 - Keratin 8 (K8) variants predispose to human liver injury via poorly understood mechanisms. We generated transgenic mice that overexpress the human disease-associated K8 Gly61-to-Cys (G61C) variant and showed that G61C predisposes to liver injury and apoptosis and dramatically inhibits K8 phosphorylation at serine 73 (S73) via stress-activated kinases. This led us to generate mice that overexpress K8 S73-to-Ala (S73A), which mimicked the susceptibility of K8 G61C mice to injury, thereby providing a molecular link between K8 phosphorylation and disease-associated mutation. Upon apoptotic stimulation, G61C and S73A hepatocytes have persistent and increased nonkeratin proapoptotic substrate phosphorylation by stress-activated kinases, compared with wild-type hepatocytes, in association with an inability to phosphorylate K8 S73. Our findings provide the first direct link between patient-related human keratin variants and liver disease predisposition. The highly abundant cytoskeletal protein K8, and possibly other keratins with the conserved S73-containing phosphoepitope, can protect tissue from injury by serving as a phosphate "sponge" for stress-activated kinases and thereby provide a novel nonmechanical function for intermediate filament proteins.

AB - Keratin 8 (K8) variants predispose to human liver injury via poorly understood mechanisms. We generated transgenic mice that overexpress the human disease-associated K8 Gly61-to-Cys (G61C) variant and showed that G61C predisposes to liver injury and apoptosis and dramatically inhibits K8 phosphorylation at serine 73 (S73) via stress-activated kinases. This led us to generate mice that overexpress K8 S73-to-Ala (S73A), which mimicked the susceptibility of K8 G61C mice to injury, thereby providing a molecular link between K8 phosphorylation and disease-associated mutation. Upon apoptotic stimulation, G61C and S73A hepatocytes have persistent and increased nonkeratin proapoptotic substrate phosphorylation by stress-activated kinases, compared with wild-type hepatocytes, in association with an inability to phosphorylate K8 S73. Our findings provide the first direct link between patient-related human keratin variants and liver disease predisposition. The highly abundant cytoskeletal protein K8, and possibly other keratins with the conserved S73-containing phosphoepitope, can protect tissue from injury by serving as a phosphate "sponge" for stress-activated kinases and thereby provide a novel nonmechanical function for intermediate filament proteins.

UR - http://www.scopus.com/inward/record.url?scp=33745628320&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33745628320&partnerID=8YFLogxK

U2 - 10.1083/jcb.200602146

DO - 10.1083/jcb.200602146

M3 - Article

VL - 174

SP - 115

EP - 125

JO - Journal of Cell Biology

JF - Journal of Cell Biology

SN - 0021-9525

IS - 1

ER -