Activation of IRF by Cytosolic Pattern Recognition Receptors


Pathway Description

Pattern recognition receptors (PRRs) recognize pathogen associated molecular patterns (PAMPs) such as lipopysaccharide or nucleic acids. The engagement of PRRs results in the activation of specific genes and subsequent triggering of innate immune responses in the host. One of the hallmarks of the innate immune response is the induction of the type 1 interferon (IFN) genes. The cytosolic PRR pathway of type 1 IFN induction involves the activation of the interferon regulatory factor (IRF) family of transcription factors.The presence of double stranded RNA (dsRNA) or double stranded DNA in the cytosol following infection by viruses or intracellular bacteria trigger the cytosolic PRR system. The key sensors of viral dsRNA are Retinoic-acid-inducible gene 1 (RIG-1) and /or Melanoma-differentiation-associated gene 5 (MDA5) proteins. The activated PRRs then interact with a mitochondrial adaptor protein -MAVS (mitochondrial antiviral signaling protein), which in turn results in the activation of TANK-binding kinase 1(TBK1) and inhibitor of kappa B kinase epsilon (IKKε). The activated kinases induce the serine phosphorylation of IRF3 and IRF7, which results in their homo or heterodimerization. These dimers translocate to the nucleus, where they activate the transcription of early phase type 1 interferons (IFNα4 and IFNβ) as well as other protein involved in the innate antiviral response. The early phase type I interferons induce the later phase of type 1 IFNs (IFN non-α4 and IFNβ) largely via IRF7 homodimers. The later phase of interferons further augments the innate immune response of the host. The adaptor protein MAVS, in addition to activating the IRF pathway also activates the NFκB pathway of type I IFN induction. Another protein that serves as a similar adaptor is the IKKγ subunit NEMO. Several host and viral proteins modulate the activation of IRFs by cytosolic PRRs. Double stranded DNA in the cytosol derived from intracellular bacteria or DNA viruses trigger the cytosolic DNA sensor /PRR DAI, resulting in an innate immune response. The interaction of DNA with DAI results in the recruitment and activation of TBK1 and IRF3. Activated and phosphorylated IRF3 homodimerizes and translocates to the nucleus where it is involved in the induction of type 1 IFNS. Activated DAI also activates NFκB which in turn induces the transcription of IL-6. Host and pathogen proteins can modulate the DNA sensing by DAI.

This pathway highlights the key molecular events involved in the activation of IRFs by cytosolic PRRs, resulting in an innate immune response against viruses and bacteria.