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. 2023 Jun 23;15(7):1422. doi: 10.3390/v15071422

Figure 1.

Figure 1

Major signaling pathways regulated by Pellino proteins. Pellino proteins act as intermediate signaling molecules between cytokine, RLR, and TLR in membranes or the cytosol, and transcription factors in the nucleus. Upon IL-1 binding, MyD88 is recruited to the membrane-bound receptor IL-1R1 and IL-1RAP. The IRAK and Pellino proteins are further engaged and promote downstream activation of the IKK (IκB-kinase) complex, which in turn phosphorylates IκB. IκB becomes ubiquitinated and is degraded. This releases the transcription factor NF-κB, which translocates to the nucleus where it activates the expression of pro-inflammatory genes. The pathway can branch to activate MAP kinases essential for activation of the transcription factors AP1 and Elk1. The same signaling cascades can be activated by extracellular TLRs, including TLR2 and TLR4, which may be involved in the recognition of several viral surface proteins. TLR3, TLR7, TLR8, and TLR9, which bind single- and double-stranded RNA and DNA present in endosomes, can activate the same pathways in an MyD88-dependent or -independent manner. The latter requires TRIF and results in interactions between Pellino proteins and the two kinases IKKε and TBK1. Through phosphorylation, this results in the activation of IRFs. The IRFs form homo- and heterodimers that in the nucleus bind to promoter regions of genes encoding type I IFNs. The Pellino•IKKε•TBK1•IRF pathway is also engaged by RLRs such as RIG-I and MDA5, which recognizes viral RNA in the cytosol. These pathways also contribute to activation of the inflammasome. Pellino primes the inflammasome through the ubiquitination of NLRP3 and ASC. IL1B is among the many immune response genes activated by NF-κB. The gene transcript is translated into pro-IL-1β, which is activated through cleavage by caspase-1 in the inflammasome. In a similar manner, GSDMD (gasdermin-D) is cleaved. The N-terminal fragment N-GSDMD oligomerizes and forms membrane pores through which IL-1β is released. These pores can also contribute to pyroptotic cell death. The specific mechanisms engaged during viral infection appear to be cell type- and context-dependent (see text for details). The individual signaling cascades and the involvement of specific Pellino proteins are more comprehensively reviewed elsewhere [3,4].