| First Author | Linares JF | Year | 2021 |
| Journal | Mol Cell | Volume | 81 |
| Issue | 21 | Pages | 4509-4526.e10 |
| PubMed ID | 34560002 | Mgi Jnum | J:315700 |
| Mgi Id | MGI:6831136 | Doi | 10.1016/j.molcel.2021.08.039 |
| Citation | Linares JF, et al. (2021) PKClambda/iota inhibition activates an ULK2-mediated interferon response to repress tumorigenesis. Mol Cell 81(21):4509-4526.e10 |
| abstractText | The interferon (IFN) pathway is critical for cytotoxic T cell activation, which is central to tumor immunosurveillance and successful immunotherapy. We demonstrate here that PKClambda/iota inactivation results in the hyper-stimulation of the IFN cascade and the enhanced recruitment of CD8(+) T cells that impaired the growth of intestinal tumors. PKClambda/iota directly phosphorylates and represses the activity of ULK2, promoting its degradation through an endosomal microautophagy-driven ubiquitin-dependent mechanism. Loss of PKClambda/iota results in increased levels of enzymatically active ULK2, which, by direct phosphorylation, activates TBK1 to foster the activation of the STING-mediated IFN response. PKClambda/iota inactivation also triggers autophagy, which prevents STING degradation by chaperone-mediated autophagy. Thus, PKClambda/iota is a hub regulating the IFN pathway and three autophagic mechanisms that serve to maintain its homeostatic control. Importantly, single-cell multiplex imaging and bioinformatics analysis demonstrated that low PKClambda/iota levels correlate with enhanced IFN signaling and good prognosis in colorectal cancer patients. |
