Faculty Collaboration Database

Mirc11 Disrupts Inflammatory but Not Cytotoxic Responses of NK Cells. Cancer Immunol Res 2019 Oct;7(10):1647-1662

Date

09/14/2019

Pubmed ID

31515257

Pubmed Central ID

PMC7428857

DOI

10.1158/2326-6066.CIR-18-0934

Scopus ID

2-s2.0-85072848720 (requires institutional sign-in at Scopus site)   10 Citations

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-γ-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-κB 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.

Author List

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

Authors

Subramaniam Malarkannan PhD Professor in the Medicine department at Medical College of Wisconsin
Sridhar Rao MD, PhD Associate Professor in the Pediatrics department at Medical College of Wisconsin
Shirng-Wern Tsaih Research Scientist II in the Obstetrics and Gynecology department at Medical College of Wisconsin
Demin Wang PhD Professor in the Microbiology and Immunology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Cells, Cultured
Cytokines
Female
Humans
Inflammation
Killer Cells, Natural
Male
Melanoma, Experimental
Mice
Mice, Inbred C57BL
Mice, Knockout
MicroRNAs
Signal Transduction
T-Lymphocytes, Cytotoxic
TNF Receptor-Associated Factor 6
Transcription Factor AP-1
Transcription Factor RelA
Ubiquitin
Ubiquitination