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

Abstract

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 α-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-Ser 44 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-Ser 44 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.

Metabolic dysfunction associated steatotic liver disease in patients with plaque psoriasis: a case–control study and serological comparison

“…Confirmation of these findings would imply that targeting CK-19 expression to inhibit cell proliferation could be a promising therapeutic strategy for psoriasis and its related conditions. These findings align with a cellular experiment on keratin-17, corroborating our understanding of keratin properties and functions ( 60 ). Although these observations suggest a potential involvement of CK-19 in immune processes and cell proliferation/apoptosis related to psoriasis and MASLD, the pathogenesis of CK-19 in these conditions is yet to be thoroughly reported.…”

Targeted siRNA Therapy for Psoriasis: Translating Preclinical Potential into Clinical Treatments

“… [ 29 , 55 ] K17 Keratinocytes Anti-K17 therapy is an effective treatment option for psoriasis, and the K17 molecule, as a new target, may hold tremendous potential for the treatment of psoriasis in the future. [ 32 ] ENO1/K17 Keratinocytes Revealed the mechanism by which K17 interacts with ENO1 to promote glycolysis and proliferation of KCs, provides a new perspective for the study of the correlation between proliferation and metabolism. [ 35 , 36 ] STAT1/STAT3 JAK/STAT Keratinocytes Silencing STAT1 and STAT3 can inhibit the proliferation of keratinocytes.…”

“…Luo et al demonstrated the interaction between KRT17 and ENO1 , which promotes glycolysis and proliferation in keratinocytes. 32 …”

CYSLTR1 antagonist inhibits Th17 cell differentiation by regulating the NF-κB signaling for the treatment of psoriasis

“…In vitro , montelukast demonstrated an inhibitory effect on M5-induced overexpression of factors associated with hyperproliferation (KI67, PCNA), inflammatory cytokines (IL-17A, IL-17F 34 , IL-6), angiogenesis (TGF-α 35 , VEGF 36 , and HIF-1α 37 ), keratogenesis (KRT16 38 , KRT17 39 , and cyclin E1 40 ), and autoimmunity (S100A12 41 , S100A15 42 , hBD-2 43 , and hBD-3 44 ) in HaCaT keratinocytes. The inhibitory effect of montelukast on HaCAT cell proliferation may be attributed to the modulation of the NF-κB signaling pathway in keratinocytes.…”