A novel transglutaminase activator forms a complex with type 1 transglutaminase

Type I transglutaminase is a plasma membrane-anchored intracellular protein–protein crosslinking enzyme that is responsible for assembly of the keratinocyte cornified envelope during terminal keratinocyte differentiation. We recently described a novel protein, TIG3, that when expressed in keratinocytes causes increased transglutaminase activity and keratinocyte cell death. However, the mechanism of activation of transglutaminase by TIG3 is not known. We now extend our previous study and show that full-length TIG3 forms a complex with type I transglutaminase that is demonstrated by TIG3-transglutaminase co-precipitation. We also demonstrate that treating TIG3-expressing cells with monodansyl cadaverine, a competitive transglutaminase substrate, attenuates the TIG3-dependent response, suggesting that transglutaminase is an important mediator of TIG3 action. These findings suggest that TIG3 forms a complex with transglutaminase resulting in transglutaminase activation and that transglutaminase activity is required for the TIG3-dependent biological response.