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Transglutaminase 2 regulates mallory body inclusion formation and injury-associated liver enlargement

Pavel Strnad1, Masaru Harada, Matthew Siegel

  • 1Department of Medicine, Palo Alto VA Medical Center, Palo Alto, California, USA.

Gastroenterology
|April 6, 2007
PubMed
Abstract

Insights

Transglutaminase 2 (TG2) is essential for Mallory body (MB) formation in liver injury. TG2 activity and keratin 8 (K8) cross-linking are required for MBs and liver enlargement.

Area of Science:

  • Hepatology
  • Cell Biology
  • Biochemistry

Background:

  • Mallory bodies (MBs) are characteristic inclusions in liver diseases, primarily composed of keratins 8 and 18 (K8/K18).
  • MB formation requires a specific K8/K18 ratio and glutamine-lysine cross-links mediated by transglutaminase (TG).

Purpose of the Study:

  • To investigate the essential role of protein transamidation, specifically TG2, in MB formation.
  • To elucidate the relationship between TG2, keratin cross-linking, and liver injury responses.

Main Methods:

  • Utilized TG2 knockout (TG2-/-) and wild-type mice treated with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC), an MB inducer.
  • Examined keratin cross-linking using recombinant proteins and transgenic mice overexpressing K8 or K18.

Main Results:

  • TG2-/- mice exhibited significantly reduced MB formation and liver hypertrophy compared to wild-type mice following DDC administration.
  • Reduced TG2 activity in TG2-/- mice correlated with decreased K8-containing protein cross-linking and ubiquitination.
  • K8 was identified as a preferential TG2 substrate over K18 in vitro and in vivo.

Conclusions:

  • TG2 plays a critical role in mediating injury-induced liver enlargement and MB formation.
  • The formation of cross-linked keratins and MBs necessitates both K8 and TG2.
  • TG-mediated cross-linking may be a common mechanism in various intermediate filament protein-related diseases.

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