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| Item Type: | Article |
|---|---|
| Title: | Phosphorylation of RAB7 by TBK1/IKKε regulates innate immune signaling in triple negative breast cancer |
| Creators Name: | Ritter, J.L., Zhu, Z., Thai, T.C., Mahadevan, N.R., Mertins, P., Knelson, E.H., Piel, B.P., Han, S., Jaffe, J.D., Carr, S.A., Barbie, D.A. and Barbie, T.U. |
| Abstract: | Triple negative breast cancer (TNBC) is a heterogeneous disease enriched for mutations in PTEN and dysregulation of innate immune signaling. Here we demonstrate that Rab7, a recently identified substrate of PTEN phosphatase activity, is also a substrate of the innate immune signaling kinases TBK1/IKKε on the same serine-72 site. An unbiased search for novel TBK1/IKKε substrates using stable isotope labeling with amino acids in cell culture (SILAC) phosphoproteomic analysis identified Rab7 serine-72 (S72) as a top hit. PTEN-null TNBC cells expressing a phosphomimetic version of Rab7-S72 exhibited diffuse cytosolic Rab7 localization and enhanced innate immune signaling, in contrast to a kinase-resistant version, which localized to active puncta that promote lysosomal-mediated STING degradation. Thus, convergence of PTEN loss and TBK1/IKKε activation on Rab7-S72 phosphorylation limited STING turnover and increased downstream production of IRF3 targets including CXL10, CCL5, and IFN-b. Consistent with this data, PTEN-null TNBC tumors expressed higher levels of STING, and PTEN-null TNBC cell lines were hyper-responsive to STING agonists. Together these findings begin to uncover how innate immune signaling is dysregulated downstream of TBK1/IKKε in a subset of TNBCs and reveals previously unrecognized cross-talk with STING recycling that may have implications for STING agonism in the clinic. |
| Keywords: | Breast, HEK293 Cells, I-kappa B Kinase, Innate Immunity, Membrane Proteins, Mutation, PTEN Phosphohydrolase, Phosphorylation, Protein-Serine-Threonine Kinases, Proteolysis, rab GTP-Binding Proteins, Serine, Signal Transduction, Site-Directed Mutagenesis, Triple Negative Breast Neoplasms, Tumor Cell Line |
| Source: | Cancer Research |
| ISSN: | 0008-5472 |
| Publisher: | American Association for Cancer Research |
| Volume: | 80 |
| Number: | 1 |
| Page Range: | 44-56 |
| Date: | January 2020 |
| Official Publication: | https://doi.org/10.1158/0008-5472.CAN-19-1310 |
| External Fulltext: | View full text on PubMed Central |
| PubMed: | View item in PubMed |
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