Tissue transglutaminase (TG2) acting as G protein protects hepatocytes against Fas-mediated cell death in mice

Zsolt Sarang, Péter Molnár, Tamás Németh, Szabolcs Gomba, Tamás Kardon, Gerry Melino, Susanna Cotecchia, László Fésüs, Zsuzsa Szondy

Research output: Article

37 Citations (Scopus)

Abstract

Tissue transglutaminase (TG2) is a protein cross-linking enzyme known to be expressed by hepatocytes and to be induced during the in vivo hepatic apoptosis program. TG2 is also a G protein that mediates intracellular signaling by the alpha-1b-adrenergic receptor (AR) in liver cells. Fas/Fas ligand interaction plays a crucial role in various liver diseases, and administration of agonistic anti-Fas antibodies to mice causes both disseminated endothelial cell apoptosis and fulminant hepatic failure. Here we report that an intraperitoneal dose of anti-Fas antibodies, which is sublethal for wild-type mice, kills all the TG2 knock-out mice within 20 hours. Although TG2-/- thymocytes exposed to anti-Fas antibodies the at the same rate as wild-type mice, TG2-/- hepatocytes show increased sensitivity toward anti-Fas treatment both in vivo and in vitro, with no change in their cell surface expression of Fas, levels of FLIPL (FLICE-inhibitory protein), or the rate of I-κBα degradation, but a decrease in the Bcl-xL expression. We provide evidence that this is the consequence of the impaired AR signaling that normally regulates the levels of Bcl-xL in the liver. In conclusion, our data suggest the involvement of adrenergic signaling pathways in the hepatic regeneration program, in which Fas ligand-induced hepatocyte proliferation with a simultaneous inhibition of the Fas-death pathway plays a determinant role.

Original languageEnglish
Pages (from-to)578-587
Number of pages10
JournalHepatology
Volume42
Issue number3
DOIs
Publication statusPublished - szept. 1 2005

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ASJC Scopus subject areas

  • Hepatology

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