title: Type I transglutaminase accumulation in the endoplasmic reticulum may be an underlying cause of autosomal recessive congenital ichthyosis.
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.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
authors.forename: Haibing
authors.initials: H
authors.lastname: Jiang
authors.forename: Ralph
authors.initials: R
authors.lastname: Jans
authors.forename: Wen
authors.initials: W
authors.lastname: Xu
authors.forename: Ellen A
authors.initials: EA
authors.lastname: Rorke
authors.forename: Chen-Yong
authors.initials: CY
authors.lastname: Lin
authors.forename: Ya-Wen
authors.initials: YW
authors.lastname: Chen
authors.forename: Shengyun
authors.initials: S
authors.lastname: Fang
authors.forename: Yongwang
authors.initials: Y
authors.lastname: Zhong
authors.forename: Richard L
authors.initials: RL
authors.lastname: Eckert
mesh_terms: D002462:Cell Membrane / Q000201:enzymology* / Q000235:genetics; D002478:Cells, Cultured; D004721:Endoplasmic Reticulum / Q000201:enzymology* / Q000235:genetics; D030342:Genetic Diseases, Inborn / Q000201:enzymology* / Q000235:genetics; D006801:Humans; D007057:Ichthyosis / Q000201:enzymology* / Q000235:genetics; D015603:Keratinocytes / Q000201:enzymology*; D008297:Male; D017354:Point Mutation; D017510:Protein Folding; D021381:Protein Transport / Q000235:genetics; D011503:Transglutaminases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination / Q000235:genetics*
chemical_list: D011503:Transglutaminases; C105804:transglutaminase 1