MicroRNA Mirc11 optimizes the inflammatory responses by silencing ubiquitin modifiers and altering K63 and K48 ubiquitylation of TRAF6

Proinflammatory cytokines produced by lymphocytes are required to contain tumor growth. Post-transcriptional mechanisms that regulate this process remains unknown. Here, we identify that the microRNA cluster Mirc11 is a central regulator of NK cell-mediated proinflammatory responses. The absence of Mirc11 only moderately reduced NK cell-mediated anti-tumor cytotoxicity. However, the loss of Mirc11 significantly reduced the generation of proinflammatory cytokines in vitro and the Interferon-γ-dependent clearance of B16F10-melanoma or Listeria monocytogenes in vivo by NK cells. We define Mirc11 optimizes inflammatory cytokine production by silencing the translation of ubiquitin modifiers A20, Cbl-b and Itch, allowing TRAF6-dependent activation of NF-κB and AP-1. A lack of Mirc11 caused an increased translation of A20, Cbl-b, and Itch proteins, resulting in the deubiquitylation of scaffolding K63 and the addition of degradative K48 moieties on TRAF6. Our results provide a novel mechanism by which Mirc11 fine tunes NF-κB and AP-1-dependent cytokine gene transcriptions and anti-tumor responses.