Regulation Of MDA5-mediated Antiviral Innate Immune Response By TRIM16

Viral invasion triggers host antiviral innate immune responses,which is the first line of host defense against invading microbial pathogens.The conserved microbial components called pathogen-associated molecular patterns(PAMPs)are sensed by cellular pattern recognition receptors(PRRs).The host cells initiate a series of signaling cascades which ultimately lead to induction of type I interferons(IFNs),pro-inflammatory cytokines,and other downstream effector genes,to inhibit microbial replication,clear infected cell and facilitate adaptive immune response.Viral nucleic acids are major PAMPs that are sensed by the host cells after viral infection.The intracellular viral RNA is detected by the retinoic acid-inducible gene-I(RIG-I)-like receptors(RLRs),including RIG-I and MDA5.RIG-I and MDA5 play crucial roles in innate immune response to different types of RNA viruses.RIG-I and MDA5 share the common adaptor protein VISA(also known as MAVS,IPS-1 or Cardif)which resides on the mitochondrial outer membrane,and they utilize similar signaling pathways to induce downstream antiviral genes.Upon binding to viral RNA released during virus replication,RIG-I or MDA5 undergoes conformational changes and is recruited to the adaptor protein VISA.The CARD modules of RIG-I and MDA5 are responsible for transmit signals to downstream CARD-containing adaptor VISA.This triggers the formation of large prion-like VISA polymers,which in turn acts as a central platform for recruitment of TRAF2/3/5/6 through its TRAF-binding motifs.The TRAF proteins further recruit TBK1/IKK complex to phosphorylate IRF3 and IκBαrespectively,leading to activation of IRF3 and NF-κB and production of type I interferons and proinflammatory cytokines.Upon viral infection,recognition of 5’-triplephosphate double-stranded RNA(5’ppp-ds RNA)or long ds RNA by the retinoic acid-inducible gene-I(RIG-I)or melanoma differentiation-associated gene 5(MDA5)respectively initiates innate antiviral immune response.Though the regulatory mechanisms of RIG-I have been intensively explored in past years,how MDA5 is regulated in innate antiviral response is not well understood.Here,we identified TRIM16 as a positive regulator of MDA5.Knockdown of TRIM16 specifically inhibited MDA5-sensed long ds RNA-and encephalomyocarditis virus(EMCV)-induced transcription of antiviral genes including IFNB1,CXCL10 and ISG56,but hardly affected that induced by RIG-I-sensed5’ppp-ds RNA and vesicular stomatitis virus(VSV).Consistently,TRIM16-deficient mice were more susceptible to EMCV infection and TRIM16 deficiency inhibited replication of EMCV in the brains of mice.Furthermore,we found that TRIM16 was associated with MDA5 post viral infection,and critical for recruitment of the downstream adaptor protein VISA to MDA5 but not RIG-I.These findings suggest that TRIM16 specifically regulates MDA5-but not RIG-I-mediated innate antiviral signaling.In this paper,we identified TRIM16 as an important positive regulator for innate antiviral immune response.Our findings provide additional regulatory molecular mechanism for MDA5,and suggest that TRIM16 might be a potential target for the drug design and treatment of infectious diseases.