Study of RIPK4 promotes epidermal differentiation through phase separation and activation of LATS1/2. Xiaolei Cao et al

The asymmetric divisions of keratinocytes along the basement membrane establish a stratified epidermis. Inactivating mutations of Receptor interacting serine/threonine kinase 4 (RIPK4) cause human developmental syndromes characterized by defective epidermal differentiation. While the Hippo pathway is crucial in limiting organ size, emerging evidence suggests that it also plays additional roles in differentiation. In this study, we identify RIPK4 as an alternative upstream kinase of LATS1/2 in the Hippo pathway through screening a kinome library. Knocking out Ripk4 results in activation of Hippo pathway effectors Yap/Taz in the mouse granular layer, which subsequently represses cholesterol biosynthesis. Furthermore, the ablation of Yap/Taz partially rescues skin barrier defects. Mechanistically, RIPK4 directly phosphorylates LATS1/2 after recruiting them into liquid condensates. Disease-derived RIPK4 mutants exhibit defects in LATS1/2 activation either due to impaired kinase activity or disrupted phase separation. Our findings demonstrate that a RIPK4-initiated noncanonical Hippo pathway plays a specific role in epidermal differentiation.