Protein kinase Cα regulates the nucleocytoplasmic shuttling of KRIT1

KRIT1 is a scaffolding protein that regulates multiple molecular mechanisms, including cell-cell and cell-matrix adhesion, and redox homeostasis and signaling. However, rather little is known about how KRIT1 is itself regulated. KRIT1 is found in both the cytoplasm and the nucleus, yet the upstream signaling proteins and mechanisms that regulate KRIT1 nucleocytoplasmic shuttling are not well understood. Here, we identify a key role for protein kinase C (PKC) in this process. In particular, we found that PKC activation promotes the redox-dependent cytoplasmic localization of KRIT1, whereas inhibition of PKC or treatment with the antioxidant N-acetylcysteine leads to KRIT1 nuclear accumulation. Moreover, we demonstrated that the N-terminal region of KRIT1 is crucial for the ability of PKC to regulate KRIT1 nucleocytoplasmic shuttling, and may be a target for PKC-dependent regulatory phosphorylation events. Finally, we found that silencing of PKC alpha, but not PKC delta, inhibits phorbol 12-myristate 13-acetate (PMA)-induced cytoplasmic enrichment of KRIT1, suggesting amajor role for PKC alpha in regulating KRIT1 nucleocytoplasmic shuttling. Overall, our findings identify PKC alpha as a novel regulator of KRIT1 subcellular compartmentalization, thus shedding new light on the physiopathological functions of this protein.

Automated summary

The study identified protein kinase C (PKC) as a key regulator of KRIT1 subcellular localization, with PKC activation promoting cytoplasmic localization of KRIT1 and PKC inhibition or antioxidant treatment leading to nuclear accumulation of KRIT1. Furthermore, the N-terminal region of KRIT1 was found to be crucial for PKC-mediated regulation of nucleocytoplasmic shuttling. Additionally, silencing of PKC alpha hindered PMA-induced cytoplasmic enrichment of KRIT1, highlighting the significant role of PKC alpha in this process.