The Role Of Mascrna In The Regulation Of Innate Immunity

Toll-like receptor(TLR)is a type of pathogen recognition receptor,which mediates innate immune response.After recognizing the corresponding ligand,TLR can trigger different types of signal transduction in cells by forming signal complexes,thereby mediating the innate immune response.As a key signal molecule in TLR-mediated signal transduction,the dysfunction of TRAF6 will cause abnormalities in TLR downstream signal transduction,leading to disturbance of the immune response.Therefore,the function of TRAF6 protein needs to be strictly regulated.MALAT1-associated small cytoplasmic RNA(mascRNA)is a highly conserved t RNA-like non-coding RNA,and its function is still largely unknown.In our study,mascRNA inhibited the activation of TLR4/2-mediated NF-κB and MAPK signaling pathways and the production of inflammatory cytokines in macrophages.In addition,the exogenous mascRNA alleviated LPS-induced lung inflammation in mice.In contrast,mascRNA increased the phosphorylation of IRF3 and STAT1 and the transcription of interferon induced by TLR3 ligand poly(I:C)in vitro and in vivo.Mechanistically,mascRNA promoted TRAF6 K48 ubiquitination and led to its degradation through proteasome pathway,thereby negatively regulating the TLR-mediated MyD88-dependent inflammatory response,while positively regulating TRIF-dependent antiviral response.Additionally,we found that hnRNP H/F protein directly interacted with mascRNA,and hnRNP H/F positively regulated TLR-mediated inflammatory response by inhibiting the expression of mascRNA.In summary,our research revealed that in addition to proteins,long non-coding RNAs and microRNAs,mascRNA also can be considered as a new type of regulatory factors involved in the regulation of innate immunity.The dual role of mascRNA in the regulation of innate immunity holds promise for developing therapeutics for the treatment of certain inflammation-related diseases since mascRNA suppresses inflammatory cytokine production without compromising IFN-based therapeutic effects on inflammation and cancer.