Nuclear innate sensors for nucleic acids in immunity and inflammation

Abstract

Innate sensors recognize pathogen‐associated molecular patterns (PAMPs) or damage‐associated molecular patterns (DAMPs) to initiate innate immune response by activating downstream signaling. These evolutionarily conserved innate sensors usually locate in the plasma membrane or cytoplasm. However, the nucleus‐localized innate sensors are recently found to detect pathogenic nucleic acids for initiating innate response, demonstrating a complicated crosstalk with cytoplasmic sensors and signaling molecules to form an elaborate tiered innate signaling network between nucleus and cytoplasm. Furthermore, these nuclear innate sensors evolve varied mechanisms for discriminating self from non‐self nucleic acids to maintain immune homeostasis and avoid autoinflammatory immune response. In this review, we summarize the recent findings on the identification of nuclear innate sensors for nucleic acids, such as hnRNPA2B1, IFI16, SAFA, and their roles in host defense and inflammatory response.

Multi-organ Proteomic Landscape of COVID-19 Autopsies

“…In our data, COVID-19 lung proteome showed unique enrichment of pathways which are known to be associated with virus infection, including mRNA decay and translation shutoff (Tanaka et al, 2012) (Figure 4C). Further, double-stranded RNA (dsRNA) and uncapped mRNA of the virus act as viral pathogen-associated molecular patterns (PAMPs) which trigger the innate immune response through recognition by pattern recognition receptors (PRRs) in the cytoplasm (Lin and Cao, 2020). By comparing with the SARS-CoV-2 protein interaction map (Gordon et al, 2020), 12 virus-host interacting proteins were dysregulated only in the lung, including stress granule-related factor G3BP1, mitochondrial protein TIM10, transcription regulator eIF4H, RING-type E3 ubiquitin ligase MIB1, pro-inflammatory cytokine receptor IL17RA, and member of Cullin RING E3 ligase 2 complex ZYG11B (Figure 4D).…”

“…During virus replication, double-stranded RNA (dsRNA) and uncapped mRNA of virus, known as viral pathogen-associated molecular patterns (PAMPs), could trigger the innate immune response once recognized by the pattern recognition receptors (PRRs) in the cytoplasm 221 . According to the PRRs list 221 , we found CGAS was upregulated in the lung of COVID-19 patients ( Figure 5A, SI Figure 10a). The upregulation of CGAS further induces downstream response including Type I interferon secretion and the release of several other cytokines 222 .…”

Multi-organ proteomic landscape of COVID-19 autopsies

“…Our data showed that EIF4E was upregulated only in the lung of the COVID-19 patients (Figure 5A), which might be perturbed and hijacked by SARS-CoV-2. Further, double-stranded RNA (dsRNA) and uncapped mRNA of the virus act as viral pathogen-associated molecular patterns (PAMPs) that trigger the innate immune response through recognition by pattern recognition receptors (PRRs) in the cytoplasm (Lin and Cao, 2020). By comparing with the SARS-CoV-2 protein interaction map (Gordon et al, 2020), 12 virus-host interacting proteins were dysregulated only in the lung, including stress granule-related factor G3BP1, mitochondrial protein TIMM10, transcription regulator eIF4H, RING-type E3 ubiquitin ligase MIB1, pro-inflammatory cytokine receptor IL17RA, and member of Cullin RING E3 ligase 2 complex ZYG11B (Figure 4D).…”

Intracellular innate immune receptors: Life inside the cell

“…NLRC1 and NLRC2, also known as NOD1 and NOD2, were the first intracellular sensors of bacterial peptidoglycan to be discovered, [51][52][53] Nuclear sensors can contribute to innate immunity by shuttling to the cytoplasm upon activation to initiate signaling cascades there, or they can perform functions directly in the nucleus and exert epigenetic control or regulate mRNA modifications. 55 Their direct nuclear action is a unique characteristic among the PRRs and may allow nuclear sensors to act more quickly than cytosolic sensors.…”

“…55 Nuclear sensors must walk a fine line to avoid aberrant activation in response to self-nucleic acids while still being ready to eliminate foreign threats. Lin and Cao cover the mechanisms employed by these sensors to ensure this important differentiation is maintainedand describe how these sensors drive innate immune signaling 55.…”