Innate immunity signaling. (A) PAMPs and PRRs. Some examples of PAMPs (red squares) and specific PRRs (blue letters) that recognize them (see Box 2 for details). PRRs are positioned on the plasma membrane, endocytic membranes, and the cytosol. TLRs on the plasma membrane and endosomes, as well as nucleic acid-sensing cytosolic PRRs such as RIG-1, MDA5, cGAS, and AIM2 are some of the most widely studied PRRs. Selected PAMPs include a variety of proteins, lipids, and nucleotides frequently found in pathogens. PAMPs include molecules such as peptidoglycan (PGN), triacyl and diacyl lipopeptides (TLP and DLP), lipoteichoic acid (LTA), lipoarabinomannan (LAM), glycosylphosphatidylinositol (GPI)-anchored mucins (tGPI-mucin), LPS, single stranded (ss) and ds nucleotides (ss and dsRNA and DNA), and CpG-containing DNA (CpG DNA). (B) Innate immunity signaling. Schematic representation of PRR signaling during innate immune activation. Only specific PRRs directly mentioned in this review are shown (TLR4 on the plasma membrane and endocytic vesicles; TLR9 in endosomes; and cGAS in the cytoplasm). When activated by a specific PAMP(s), each PRR recruits a set of accessory proteins and transduces danger signals into signaling molecules that relay responses through a series of intricate post-translational modifications. Activated signaling molecules, in turn, activate transcription factors (yellow boxes) promoting expression of inflammatory cytokines, type I IFN, and a range of antimicrobial defense genes. Cytokines (including ILs, TNF, and IFNs) function in autocrine, paracrine, and endocrine communication networks to activate other receptors, accessory proteins, kinases, and transcription factors in neighboring or distant cells (C and D). Recommended reviews to seek further details of these pathways have been included in the text. (C) IFN signaling. Binding of IFNs to their cognate receptors, IFNAR-1 and -2 (for type I IFN) and IFNGR1 and 2 (for type II IFN), transduces signals into kinases and transcription factors (yellow boxes) to promote expression of ISGs via ISREs or γ IFN activation sites (GASs) in their promoters. Proteins such as IRFs, PRRs, and viperin are expressed in response to IFNs (Schneider et al., 2014). LD proteins such as Plin2 and Plin5 are also regulated by IFN (Bosch et al., 2020b). (D) Cytokine signaling. Two representative examples of cytokines are included. IL-1 and TNFα bind to their specific receptors on the plasma membrane to activate the signaling machinery and transcription factors, for inflammatory gene expression.
Figure 2.

Innate immunity signaling. (A) PAMPs and PRRs. Some examples of PAMPs (red squares) and specific PRRs (blue letters) that recognize them (see Box 2 for details). PRRs are positioned on the plasma membrane, endocytic membranes, and the cytosol. TLRs on the plasma membrane and endosomes, as well as nucleic acid-sensing cytosolic PRRs such as RIG-1, MDA5, cGAS, and AIM2 are some of the most widely studied PRRs. Selected PAMPs include a variety of proteins, lipids, and nucleotides frequently found in pathogens. PAMPs include molecules such as peptidoglycan (PGN), triacyl and diacyl lipopeptides (TLP and DLP), lipoteichoic acid (LTA), lipoarabinomannan (LAM), glycosylphosphatidylinositol (GPI)-anchored mucins (tGPI-mucin), LPS, single stranded (ss) and ds nucleotides (ss and dsRNA and DNA), and CpG-containing DNA (CpG DNA). (B) Innate immunity signaling. Schematic representation of PRR signaling during innate immune activation. Only specific PRRs directly mentioned in this review are shown (TLR4 on the plasma membrane and endocytic vesicles; TLR9 in endosomes; and cGAS in the cytoplasm). When activated by a specific PAMP(s), each PRR recruits a set of accessory proteins and transduces danger signals into signaling molecules that relay responses through a series of intricate post-translational modifications. Activated signaling molecules, in turn, activate transcription factors (yellow boxes) promoting expression of inflammatory cytokines, type I IFN, and a range of antimicrobial defense genes. Cytokines (including ILs, TNF, and IFNs) function in autocrine, paracrine, and endocrine communication networks to activate other receptors, accessory proteins, kinases, and transcription factors in neighboring or distant cells (C and D). Recommended reviews to seek further details of these pathways have been included in the text. (C) IFN signaling. Binding of IFNs to their cognate receptors, IFNAR-1 and -2 (for type I IFN) and IFNGR1 and 2 (for type II IFN), transduces signals into kinases and transcription factors (yellow boxes) to promote expression of ISGs via ISREs or γ IFN activation sites (GASs) in their promoters. Proteins such as IRFs, PRRs, and viperin are expressed in response to IFNs (Schneider et al., 2014). LD proteins such as Plin2 and Plin5 are also regulated by IFN (Bosch et al., 2020b). (D) Cytokine signaling. Two representative examples of cytokines are included. IL-1 and TNFα bind to their specific receptors on the plasma membrane to activate the signaling machinery and transcription factors, for inflammatory gene expression.

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