Abstract
UV irradiation elicits acute inflammation in the skin by increasing proinflammatory cytokine production in keratinocytes. However, the downstream protein target(s) that link UV radiation to the activation of signaling pathways responsible for cytokine expression have not been fully elucidated. In this study, we report a novel role of transglutaminase 2 (TG2), a member of the TG enzyme family whose activities are critical for cornified envelope formation, in mediating UV-induced inflammation. Our results showed that TG2-deficient mice exhibited reduced inflammatory responses to UV irradiation, including reduced erythema, edema, dilation of blood vessels, inflammatory cell infiltration, and levels of inflammatory cytokines. Using primary mouse keratinocytes and HaCaT cells, we found that UV irradiation-induced cytokine production by activating TG2, but not by upregulating TG2 expression, and that ER calcium release triggered by the UV-induced activation of phospholipase C was required for TG2 activation. Moreover, TG2 activity enhanced p65 phosphorylation, leading to an increase in NF-κB transcriptional activity. These results indicate that TG2 is a critical mediator of cytokine expression in the UV-induced inflammatory response of keratinocytes, and suggest that TG2 inhibition might be useful for preventing UV-related skin disorders, such as photoaging and skin cancer caused by chronic UV exposure.
Highlights
Transglutaminases (TGs) are a family of calcium-dependent enzymes that produce crosslinked, polyaminated, or deamidated proteins by catalyzing the acyl-transfer reaction between the glutamine and lysine residues of substrate proteins or polyamines.[1]
To test whether TG2 is involved in this process, we examined the skin barrier function of TG2− / − mice
These results indicate that TG2 activity is not required for the differentiation or cornified envelope (CE) formation of epidermal keratinocytes
Summary
Transglutaminases (TGs) are a family of calcium-dependent enzymes that produce crosslinked, polyaminated, or deamidated proteins by catalyzing the acyl-transfer reaction between the glutamine and lysine residues of substrate proteins or polyamines.[1]. TG1-null mice displayed defective CE formation in their stratum corneum and impaired skin barrier function, leading to death within 4–5 h after birth due to dehydration.[4] TG1 mutations are the most common cause of autosomal recessive congenital ichthyosis in humans,[5] indicating that the crosslinking activity of TG1 plays a crucial role in epidermal barrier formation. Factor XIIIa-deficient mice showed delayed and defective wound healing, indicating that the crosslinking activity of factor XIIIa plays a role in wound repair and remodeling.[13] Unlike these TG isozymes, TG2-null mice showed no obvious altered skin phenotypes, despite their expression in epidermal keratinocytes.[14] there is no report of human skin disease associated with TG2. These findings indicate that TG2 functions as a stress responsive enzyme, modulating cellular functions through the modification of various substrate proteins.[1]
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