MIRC11 disrupts inflammatory but not cytotoxic responses of NK cells

Arash Nanbakhsh, Anupallavi Srinivasamani, Sandra Holzhauer, Matthew J. Riese, Yongwei Zheng, Demin Wang, Robert Burns, Michael H. Reimer, Sridhar Rao, Angela Lemke, Shirng Wern Tsaih, Michael J. Flister, Shunhua Lao, Richard Dahl, Monica S. Thakar, Subramaniam Malarkannan

Research output: Contribution to journalArticle

Abstract

Natural killer (NK) cells generate proinflammatory cytokines that are required to contain infections and tumor growth. However, the posttranscriptional mechanisms that regulate NK cell functions are not fully understood. Here, we define the role of the microRNA cluster known as Mirc11 (which includes miRNA-23a, miRNA-24a, and miRNA-27a) in NK cell–mediated proinflammatory responses. Absence of Mirc11 did not alter the development or the antitumor cytotoxicity of NK cells. However, loss of Mirc11 reduced generation of proinflammatory factors in vitro and interferon-g–dependent clearance of Listeria monocytogenes or B16F10 melanoma in vivo by NK cells. These functional changes resulted from Mirc11 silencing ubiquitin modifiers A20, Cbl-b, and Itch, allowing TRAF6-dependent activation of NF-kB and AP-1. Lack of Mirc11 caused increased translation of A20, Cbl-b, and Itch proteins, resulting in deubiquitylation of scaffolding K63 and addition of degradative K48 moieties on TRAF6. Collectively, our results describe a function of Mirc11 that regulates generation of proinflammatory cytokines from effector lymphocytes.

Original languageEnglish (US)
Pages (from-to)1647-1662
Number of pages16
JournalCancer Immunology Research
Volume7
Issue number10
DOIs
StatePublished - Jan 1 2019

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MicroRNAs
Natural Killer Cells
TNF Receptor-Associated Factor 6
Cytokines
NF-kappa B
Transcription Factor AP-1
Listeria monocytogenes
Ubiquitin
Interferons
Melanoma
Lymphocytes
Growth
Infection
Neoplasms
Proteins

ASJC Scopus subject areas

  • Immunology
  • Cancer Research

Cite this

Nanbakhsh, A., Srinivasamani, A., Holzhauer, S., Riese, M. J., Zheng, Y., Wang, D., ... Malarkannan, S. (2019). MIRC11 disrupts inflammatory but not cytotoxic responses of NK cells. Cancer Immunology Research, 7(10), 1647-1662. https://doi.org/10.1158/2326-6066.CIR-18-0934

MIRC11 disrupts inflammatory but not cytotoxic responses of NK cells. / Nanbakhsh, Arash; Srinivasamani, Anupallavi; Holzhauer, Sandra; Riese, Matthew J.; Zheng, Yongwei; Wang, Demin; Burns, Robert; Reimer, Michael H.; Rao, Sridhar; Lemke, Angela; Tsaih, Shirng Wern; Flister, Michael J.; Lao, Shunhua; Dahl, Richard; Thakar, Monica S.; Malarkannan, Subramaniam.

In: Cancer Immunology Research, Vol. 7, No. 10, 01.01.2019, p. 1647-1662.

Research output: Contribution to journalArticle

Nanbakhsh, A, Srinivasamani, A, Holzhauer, S, Riese, MJ, Zheng, Y, Wang, D, Burns, R, Reimer, MH, Rao, S, Lemke, A, Tsaih, SW, Flister, MJ, Lao, S, Dahl, R, Thakar, MS & Malarkannan, S 2019, 'MIRC11 disrupts inflammatory but not cytotoxic responses of NK cells', Cancer Immunology Research, vol. 7, no. 10, pp. 1647-1662. https://doi.org/10.1158/2326-6066.CIR-18-0934
Nanbakhsh A, Srinivasamani A, Holzhauer S, Riese MJ, Zheng Y, Wang D et al. MIRC11 disrupts inflammatory but not cytotoxic responses of NK cells. Cancer Immunology Research. 2019 Jan 1;7(10):1647-1662. https://doi.org/10.1158/2326-6066.CIR-18-0934
Nanbakhsh, Arash ; Srinivasamani, Anupallavi ; Holzhauer, Sandra ; Riese, Matthew J. ; Zheng, Yongwei ; Wang, Demin ; Burns, Robert ; Reimer, Michael H. ; Rao, Sridhar ; Lemke, Angela ; Tsaih, Shirng Wern ; Flister, Michael J. ; Lao, Shunhua ; Dahl, Richard ; Thakar, Monica S. ; Malarkannan, Subramaniam. / MIRC11 disrupts inflammatory but not cytotoxic responses of NK cells. In: Cancer Immunology Research. 2019 ; Vol. 7, No. 10. pp. 1647-1662.
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