Protein kinase Cα regulates the nucleocytoplasmic shuttling of KRIT1.
Protein kinase Cα regulates the nucleocytoplasmic shuttling of KRIT1.
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蛋白激酶Cα调节KRIT 1的核质穿梭。
DOI：
10.1242/jcs.250217
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发表时间：
2021-02-04
影响因子：
4
通讯作者：
Retta SF
中科院分区：
文献类型：
--
作者：
De Luca E;Perrelli A;Swamy H;Nitti M;Passalacqua M;Furfaro AL;Salzano AM;Scaloni A;Glading AJ;Retta SF
KRIT 1是一种支架蛋白，调节多种分子机制，包括细胞-细胞和细胞-基质粘附，氧化还原稳态和信号传导。然而，关于KRIT 1本身是如何调节的，我们知之甚少。KRIT 1存在于细胞质和细胞核中，但调控KRIT 1核质穿梭的上游信号蛋白和机制尚未完全了解。在这里，我们确定了蛋白激酶C（PKC）在这一过程中的关键作用。特别是，我们发现，PKC激活促进KRIT 1的氧化还原依赖性细胞质定位，而抑制PKC或用抗氧化剂N-乙酰半胱氨酸处理导致KRIT 1核积累。此外，我们证明了KRIT 1的N-末端区域对于PKC调节KRIT 1核质穿梭的能力至关重要，并且可能是PKC依赖性调节磷酸化事件的靶点。最后，我们发现，沉默PKCα，而不是PKCδ，抑制佛波酯12-肉豆蔻酸酯13-乙酸酯（PMA）诱导的KRIT 1的细胞质富集，这表明PKCα在调节KRIT 1核质穿梭中的主要作用。总体而言，我们的研究结果确定PKCα作为KRIT 1亚细胞区室化的一种新的调节剂，从而对这种蛋白质的生理病理学功能提供了新的认识。总结：PKC信号在触发Ser/Thr磷酸化和调节KRIT 1核质穿梭中的新作用，KRIT 1是与人类疾病相关的具有多效性功能的主要蛋白质。
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 PKCα, but not PKCδ, inhibits phorbol 12-myristate 13-acetate (PMA)-induced cytoplasmic enrichment of KRIT1, suggesting a major role for PKCα in regulating KRIT1 nucleocytoplasmic shuttling. Overall, our findings identify PKCα as a novel regulator of KRIT1 subcellular compartmentalization, thus shedding new light on the physiopathological functions of this protein. Summary: A novel role for PKC signaling in triggering Ser/Thr phosphorylation and regulating nucleocytoplasmic shuttling of KRIT1, a major protein with pleiotropic functions associated with human diseases.