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Type I transglutaminase accumulation in the endoplasmic reticulum may be an underlying cause of autosomal recessive congenital ichthyosis

Lookup NU author(s): Dr Ralph Jans

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Abstract

Type I transglutaminase (TG1) is an enzyme that is responsible for assembly of the keratinocyte cornified envelope. Although TG1 mutation is an underlying cause of autosomal recessive congenital ichthyosis, a debilitating skin disease, the pathogenic mechanism is not completely understood. In the present study we show that TG1 is an endoplasmic reticulum (ER) membrane-associated protein that is trafficked through the ER for ultimate delivery to the plasma membrane. Mutation severely attenuates this processing and a catalytically inactive point mutant, TG1-FLAG(C377A), accumulates in the endoplasmic reticulum and in aggresome-like structures where it is ubiquitinylated. This accumulation results from protein misfolding, as treatment with a chemical chaperone permits it to exit the endoplasmic reticulum and travel to the plasma membrane. ER accumulation is also observed for ichthyosis-associated TG1 mutants. Our findings suggest that misfolding of TG1 mutants leads to ubiquitinylation and accumulation in the ER and aggresomes, and that abnormal intracellular processing of TG1 mutants may be an underlying cause of ichthyosis. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.


Publication metadata

Author(s): Jiang H, Jans R, Xu W, Rorke E, Lin C, Chen Y, Fang S, Zhong Y, Eckert R

Publication type: Article

Publication status: Published

Journal: Journal of Biological Chemistry

Year: 2010

Volume: 285

Issue: 41

Pages: 31634-31646

Print publication date: 27/07/2010

ISSN (print): 0021-9258

ISSN (electronic): 1083-351X

Publisher: American Society for Biochemistry and Molecular Biology, Inc.

URL: http://dx.doi.org/10.1074/jbc.M110.128645

DOI: 10.1074/jbc.M110.128645

PubMed id: 20663883


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Funding

Funder referenceFunder name
R01 AR049713National Institutes of Health

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