Abstract
MALAT1-associated small cytoplasmic RNA (mascRNA) is a highly conserved transfer RNA–like (tRNA-like) noncoding RNA whose function remains largely unknown. We show here that this small RNA molecule played a role in the stringent control of TLR-mediated innate immune responses. mascRNA inhibited activation of NF-κB and mitogen-activated protein kinase (MAPK) signaling and the production of inflammatory cytokines in macrophages stimulated with LPS, a TLR4 ligand. Furthermore, exogenous mascRNA alleviated LPS-induced lung inflammation. However, mascRNA potentiated the phosphorylation of IRF3 and STAT1 and the transcription of IFN-related genes in response to the TLR3 ligand poly(I:C) both in vitro and in vivo. Mechanistically, mascRNA was found to enhance K48-linked ubiquitination and proteasomal degradation of TRAF6, thereby negatively regulating TLR-mediated MyD88-dependent proinflammatory signaling while positively regulating TRIF-dependent IFN signaling. Additionally, heterogeneous nuclear ribonucleoprotein H (hnRNP H) and hnRNP F were found to interact with mascRNA, promote its degradation, and contribute to the fine-tuning of TLR-triggered immune responses. Taken together, our data identify a dual role of mascRNA in both negative and positive regulation of innate immune responses.
Highlights
Toll-like receptors (TLRs) are evolutionarily ancient pattern recognition receptors that function in innate immunity against pathogens
Compared with RAW264.7 cells transfected with nonspecific antisense oligonucleotides (ASOs) (NC ASO), knockdown of mascRNA markedly increased the expression of Tnf and Il6 at both mRNA and protein levels following LPS stimulation (Figure 1, B and C)
We demonstrated that mascRNA negatively regulates TLR4/2-triggered MyD88dependent NF-ĸB and mitogen-activated protein kinase (MAPK) signaling to suppress proinflammatory cytokine production, and this tRNA-like RNA has an anti-inflammatory activity both in vitro and in vivo
Summary
Toll-like receptors (TLRs) are evolutionarily ancient pattern recognition receptors that function in innate immunity against pathogens. TRAF6 functions with an E2 ubiquitinligase complex of Ubc and Uev1A to generate K63-linked polyubiquitin chains on itself and other proteins [1, 3,4,5] These ubiquitin chains act as a scaffold to recruit and activate downstream kinase complexes containing, for instance, TAK1. As a key adaptor protein in inflammatory signaling pathways, TRAF6 activity must be tightly regulated Several deubiquitinases, such as CYLD, A20, Otud7b, USP2a, USP4, USP20 and MYSM1, are known to inhibit TRAF6 activity by directly removing its K63-linked ubiquitin chains [6]. MascRNA is a highly conserved tRNA-like small noncoding RNA with a size of 61 nucleotides [17] It is derived from post-transcriptional processing of the precursor of a lncRNA named MALAT1. We provide evidence that mascRNA, whose abundance is influenced by hnRNP H and hnRNP F (hnRNP H/F), promotes K48-linked ubiquitination of TRAF6 to fine-tune TLR-induced innate immune responses
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