PERK protein kinase facilitates keratinocyte collective cell migration by engagement with cell adhesion molecules, independent of its kinase activity

Successful cutaneous wound healing requires reepithelialization by keratinocytes using a coordinated migratory process called keratinocyte collective cell migration (KCCM). Environmental stresses such as wounding induce the integrated stress response (ISR) initiated by protein kinases that phosphorylate the α subunit of eIF2 and mitigate translational control to alleviate stress damage. We previously reported that the ISR protein kinase GCN2 (EIF2AK4) facilitates KCCM via sustained phosphorylation of eIF2α and coordinated production of reactive oxygen species and amino acid transport. In this study, we show that a second ISR protein kinase, PERK (EIF2AK3), also contributes to KCCM. PERK promotes KCCM by protein-protein interactions requiring the cytoplasmic portion of PERK but independent of its catalytic functions. To discern these PERK interactions, we used BioID proximity labeling, immunoprecipitation analyses, and immunofluorescence microscopy to show that PERK interacts with multiple cell adhesion and cytoskeletal complexes important for KCCM. PERK engages with the hemidesmosome proteins ITGA6, ITGB4, COLXVII, and the desmosome proteins JUP, DSG2, and DSG3. Loss of PERK disrupts expression and localization of these cell adhesion proteins, which alters keratinocyte morphology and increases cell-substrate and intercellular adhesions. Our results define an underappreciated scaffolding function for PERK involving cell adhesions that are critical for KCCM.