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Phosphorylation of RAB7 by TBK1/IKKε regulates innate immune signaling in triple negative breast cancer

Item Type:Article
Title:Phosphorylation of RAB7 by TBK1/IKKε regulates innate immune signaling in triple negative breast cancer
Creators Name:Ritter, J.L. and Zhu, Z. and Thai, T.C. and Mahadevan, N.R. and Mertins, P. and Knelson, E.H. and Piel, B.P. and Han, S. and Jaffe, J.D. and Carr, S.A. and 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
Publisher:American Association for Cancer Research
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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