The phosphatase regulator NIPP1 restrains chemokine-driven inflammation and DNA-damage repair in the skin

Korte inhoud:NIPP1 is a highly conserved protein of which the C-terminal two thirds are intrinsically disordered and bind to protein serine/threonine phosphatase 1 (PP1). In contrast, the N-terminal third of NIPP1 comprises a highly structured ForkHead-Associated (FHA) domain that recruits phosphorylated proteins for regulated dephosphorylation by associated PP1. Consistent with the diversity of its FHA ligands, NIPP1 has been implicated in pre-mRNA splicing, Polycomb-mediated gene repression and DNA repair. Moreover, NIPP1 is indispensable for early mouse embryonic development since NIPP1-null embryos die around the onset of gastrulation (E6.5). The deletion of NIPP1 in liver epithelial cells in mice causes the hyperproliferation of biliary epithelial cells, whereas the testis-specific deletion of NIPP1 causes reduced proliferation and survival of male germ cells. To gain further insights into the cell-type specific functions of NIPP1, including proliferation, differentiation and DNA-damage signaling, I investigated the consequences of the targeted deletion of NIPP1 in keratinocytes of mouse skin. NIPP1-deficient epidermis was characterized by hyperproliferation, a reduced adherence of basal keratinocytes and a reduced number and stemness of hair follicle stem cells, resulting in hair loss. Upon NIPP1 depletion, keratinocytes spontaneously and constitutively released proinflammatory chemokines and other immunomodulatory proteins, culminating in the recruitment of immune cells to the (epi)dermis, in particular conventional dendritic cells and Langerhans cells. The complex phenotype associated with chronic sterile inflammation could be partially rescued by dexamethasone treatment. Furthermore, the absence of NIPP1 in skin epidermis rendered mice resistant to DMBA/TPA induced skin carcinoma. Deletion of NIPP1 did not affect the metabolism of DMBA and even enhanced the proliferative effect of TPA, but reduced the conversion of DMBA-induced covalent DNA modifications into oncogenic Hras mutations in codon 61. The reduced sensitivity to DMBA correlated with an enhanced DNA-damage response and an increased DNA-repair capacity, demonstrated by the augmented expression of rate-limiting DNA-repair proteins, including the helicase XPD and the endonuclease XPG. In conclusion, our data identify NIPP1 as a key regulator of epidermal homeostasis and as a repressor of DNA repair. Our findings identify NIPP1 as a promising target for the treatment of inflammatory skin disorders as well as for novel cancer prevention and treatment therapies.

Jaar van publicatie:2019

Toegankelijkheid:Closed