Keratin 17 covalently binds to alpha-enolase and exacerbates proliferation of keratinocytes in psoriasis

Dysregulated glucose metabolism is an important characteristic of psoriasis. Cytoskeletal protein keratin 17 (K17) is highly expressed in the psoriatic epidermis and contributes to psoriasis pathogenesis. However, whether K17 is involved in the dysregulated glucose metabolism of keratinocytes (KCs) in psoriasis remains unclear. In the present study, loss-and gain-of-function studies showed that elevated K17 expression was critically involved in glycolytic pathway activation in psoriatic KCs. The level of & alpha;-enolase (ENO1), a novel potent interaction partner of K17, was also elevated in psoriatic KCs. Knockdown of ENO1 by siRNA or inhibition of ENO1 activity by the inhibitor ENOBlock remarkably suppressed KCs glycolysis and proliferation. Moreover, ENO1 directly interacted with K17 and maintained K17-Ser44 phosphorylation to promote the nuclear translocation of K17, which promoted the transcription of the key glycolysis enzyme lactic dehydrogenase A (LDHA) and resulted in enhanced KCs glycolysis and proliferation in vitro. Finally, either inhibiting the expression and activation of ENO1 or repressing K17-Ser44 phosphorylation significantly alleviated the IMQ-induced psoriasis-like phenotype in vivo. These findings provide new insights into the metabolic profile of psoriatic KCs and suggest that modulation of the ENO1-K17-LDHA axis is a potentially innovative therapeutic approach to psoriasis.

Automated summary

The dysregulated glucose metabolism in psoriasis is influenced by the cytoskeletal protein keratin 17 (K17) and its interaction partner & alpha;-enolase (ENO1). Increased K17 expression activates the glycolytic pathway in psoriatic keratinocytes (KCs). Inhibition of ENO1 or K17-Ser44 phosphorylation suppresses glycolysis and proliferation in KCs. Modulation of the ENO1-K17-LDHA axis could be a potential therapeutic approach for psoriasis.