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

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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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