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The study shows that the HIV-1 Nef protein stabilizes actin, thereby preventing R12C release and priming of RIG-I–like receptors. HIV-1 containing a mutant Nef unable to bind the actinmodulating kinase PAK2, triggers enhanced interferon responses.

In this Comment, Michaela Gack and colleagues discuss how the dysregulation of type I interferon responses may contribute to COVID-19 pathology.

RIG-I is a cytosolic RNA sensor. Gack and colleagues show that herpesviruses, duplex DNA viruses, also activate RIG-I by inducing cytoplasmic translocation and unmasking of an endogenous host 5S ribosomal pseudogene RNA, RNA5SP141.

14-3-3ɛ serves a crucial function in antiviral immunity by mediating the translocation of RIG-I from the cytosol to mitochondria. Chan and Gack have found that the NS3 protein of Dengue virus binds to 14-3-3ɛ via a highly conserved phosphomimetic motif and thereby blocks RIG-I translocation and antiviral signaling.

Here, Khan et al. identify a pan-genome-end sarbecoviral RNA element in SARS-CoV-2 that recruits an unconventional host multiprotein-complex to enhance viral translation and assigns a new function to ORF10. Antisense targeting of the element points to a potential novel therapeutic modality.

Pattern recognition receptors (PRRs) detect conserved molecular features of viral pathogens and initiate signalling that results in the expression of antiviral genes. In this Review, Chan and Gack highlight the major classes of intracellular viral RNA and DNA sensors and discuss the viral strategies that are used to escape immune surveillance by those sensors.

Bats carry viral pathogens that typically do not lead to severe disease in the bats themselves but can be lethal to humans. Adaptations in certain immune genes might contribute to this resistance.

The RNA-sensing retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) are important inducers of type I interferons and other antiviral immune mediators. Here, Jan Rehwinkel and Michaela Gack explain how members of the RLR family are regulated and reflect on the importance of the RLRs in viral infection, autoimmunity and cancer.

The cGAS-STING pathway senses cytosolic DNA to activate interferon responses, but has also been implicated in autophagy induction. Here the authors show that, during herpes simplex virus infection, cGAS-induced autophagy is mediated by TBK1-induced TRIM23 phosphorylation and downstream signaling events to assist in antiviral immunity.

ISG15 conjugation is essential to activate the RIG-I-like receptor MDA5 and trigger antiviral responses. SARS-CoV-2 suppresses MDA5 activation by direct PLpro-mediated de-ISGylation to escape innate immunity.

The sensor cyclic GMP–AMP synthase (cGAS) is well known to recognize viral DNA. In this issue of Nature Microbiology, infection by dengue virus (DENV), which has an RNA genome, is shown to induce mitochondrial DNA release into the cytosol, leading to cGAS activation. In turn, DENV targets cGAS to evade antiviral immunity.

Variants of the 3′−5′ exonuclease TREX1 can cause retinal vasculopathy with cerebral leukoencephalopathy (RVCL). Here, the authors show that RVCL-associated TREX1 variants trigger DNA damage in humans, mice, and Drosophila, and render cells more vulnerable to DNA damage inducing agents.

Mice lacking A Disintegrin and Metalloproteinase 9 (ADAM9) do not mount Type 1 interferon responses against encephalomyocarditis infection. Here, Bazzone et al show that ADAM9 regulates innate immune responses via by MDA5.

The cytoplasmic receptor RIG-I recognizes viral RNAs and initiates a protective innate immune response against a number of important viruses. Here, it is shown that RIG-I is regulated by ubiquitination.

A unique guanosine-flanked Y-form DNA triggers innate cGAS-dependent responses that lead to upregulation of the production of type I interferons.

Current high-throughput single-cell transcriptomic methods are incompatible with paraformaldehyde, a common cell fixation technique. Here the authors present FD-seq, a method for droplet-based RNA sequencing of paraformaldehyde-fixed, stained and sorted single cells.

The oncogenic Kaposi’s sarcoma-associated herpesvirus (KSHV) is known to reprogram cellular metabolism. Here, Wan et al show that viral Cyclin exploits host nucleotide synthesis and glycolysis to support KSHV pathogenesis.

ISGylation plays a crucial role in the innate immune response and requires sequential activity of E1, E2, and E3 enzymes. Here, the authors present cyro-EM structures that reveal the molecular mechanisms underlying ISG15 activation by the E1 enzyme Uba7 and transfer to its cognate E2 enzyme UBE2L6.

The E3 ligase TRIM43 ubiquitinates the centrosomal protein pericentrin, targeting it for proteasomal degradation, leading to alterations of the nuclear lamina that repress active viral chromatin states of a range of herpesviruses.

Comparisons of a chimeric recombinant version of SARS-CoV-2, the ancestral SARS-CoV-2 strain and an Omicron isolate show that the attenuated virulence of Omicron is caused by mutations in both the spike protein and nsp6.

TRIM23 is identified as an essential regulator of virus-induced autophagy that mediates restriction to several RNA and DNA viruses. K27-mediated ubiquitylation activates TRIM23 GTPase activity, triggering its relocalization and selective autophagy.

Comparative analysis of SARS-CoV-2 isolates uncovers important mutations outside the spike gene that help the Alpha variant to operate under the radar of innate immune surveillance.

A key step of the antiviral immune response is detection of the viral intruder. Infection with highly pathogenic strains of influenza virus is now shown to produce short aberrant viral RNAs that potently trigger activation of innate immunity.