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Nucleotide-binding oligomerization domain (NOD) and leucine-rich repeat (LRR)-containing receptors or NOD-like receptors (NLRs) are cytosolic pattern recognition receptors which sense conserved microbial patterns and host-derived danger signals to elicit innate immune responses. The activation of several prototypic NLRs, including NLR and pyrin domain (PYD) containing (NLRP) 1, NLRP3 and NLR and caspase recruitment domain (CARD) containing (NLRC) 4, results in the assembly of inflammasomes which are large, cytoplasmic multi-protein signaling platforms responsible for the maturation and release of the pro-inflammatory cytokines IL-1β and IL-18, and for the induction of a specialized form of inflammatory cell death called pyroptosis. However, the function of other members of the NLR family, including NLRP7, are less well understood. NLRP7 has been linked to innate immune signaling, but its precise role is still controversial as it has been shown to positively and negatively affect inflammasome responses. Inflammasomes are essential for homeostasis and host defense, but inappropriate inflammasome responses due to hereditary mutations and somatic mosaicism in inflammasome components and defective regulation has been linked to a broad spectrum of human diseases. A compelling connection between NLRP7 mutations and reproductive diseases, and in particular molar pregnancy, has been established. Though, the molecular mechanisms by which NLRP7 mutations contribute to reproductive diseases are largely unknown. In this review, we focus on NLRP7 and discuss the current evidence of its role in inflammasome regulation as well as its implication in human reproductive diseases.

Newly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused a global pandemic with astonishing mortality and morbidity. The high replication and transmission of SARS-CoV-2 are remarkably distinct from those of previous closely related coronaviruses, and the underlying molecular mechanisms remain unclear. The innate immune defense is a physical barrier that restricts viral replication. We report here that the SARS-CoV-2 Nsp5 main protease targets RIG-I and mitochondrial antiviral signaling (MAVS) protein via two distinct mechanisms for inhibition. Specifically, Nsp5 cleaves off the 10 most-N-terminal amino acids from RIG-I and deprives it of the ability to activate MAVS, whereas Nsp5 promotes the ubiquitination and proteosome-mediated degradation of MAVS. As such, Nsp5 potently inhibits interferon (IFN) induction by double-stranded RNA (dsRNA) in an enzyme-dependent manner. A synthetic small-molecule inhibitor blunts the Nsp5-mediated destruction of cellular RIG-I and MAVS and processing of SARS-CoV-2 nonstructural proteins, thus restoring the innate immune response and impeding SARS-CoV-2 replication. This work offers new insight into the immune evasion strategy of SARS-CoV-2 and provides a potential antiviral agent to treat CoV disease 2019 (COVID-19) patients. IMPORTANCE The ongoing COVID-19 pandemic is caused by SARS-CoV-2, which is rapidly evolving with better transmissibility. Understanding the molecular basis of the SARS-CoV-2 interaction with host cells is of paramount significance, and development of antiviral agents provides new avenues to prevent and treat COVID-19 diseases. This study describes a molecular characterization of innate immune evasion mediated by the SARS-CoV-2 Nsp5 main protease and subsequent development of a small-molecule inhibitor.

The balance between NLRP3 inflammasome activation and mitophagy is essential for homeostasis and cellular health, but this relationship remains poorly understood. Here we found that interleukin-1α (IL-1α)–deficient macrophages have reduced caspase-1 activity and diminished IL-1β release, concurrent with reduced mitochondrial damage, suggesting a role for IL-1α in regulating this balance. LPS priming of macrophages induced pro-IL-1α translocation to mitochondria, where it directly interacted with mitochondrial cardiolipin (CL). Computational modeling revealed a likely CL binding motif in pro-IL-1α, similar to that found in LC3b. Thus, binding of pro-IL-1α to CL in activated macrophages may interrupt CL-LC3b–dependent mitophagy, leading to enhanced Nlrp3 inflammasome activation and more robust IL-1β production. Mutation of pro-IL-1α residues predicted to be involved in CL binding resulted in reduced pro-IL-1α–CL interaction, a reduction in NLRP3 inflammasome activity, and increased mitophagy. These data identify a function for pro-IL-1α in regulating mitophagy and the potency of NLRP3 inflammasome activation.

Herpesviruses constitute a large family of disease-causing DNA viruses. Each herpesvirus strain is capable of infecting particular organisms with a specific cell tropism. Upon infection, pattern recognition receptors (PRRs) recognize conserved viral features to trigger signaling cascades that culminate in the production of interferons and pro-inflammatory cytokines. To invoke a proper immune response while avoiding collateral tissue damage, signaling proteins involved in these cascades are tightly regulated by post-translational modifications (PTMs). Herpesviruses have developed strategies to subvert innate immune signaling pathways in order to ensure efficient viral replication and achieve persistent infection. The ability of these viruses to control the proteins involved in these signaling cascades post-translationally, either directly via virus-encoded enzymes or indirectly through the deregulation of cellular enzymes, has been widely reported. This ability provides herpesviruses with a powerful tool to shut off or restrict host antiviral and inflammatory responses. In this review, we highlight recent findings on the herpesvirus-mediated post-translational control along PRR-mediated signaling pathways.

Metabolic enzymes fuel the synthesis of macromolecules that underpin the proliferation of cells and propagation of pathogens. NAD is a key cofactor for enzymes catalyzing metabolic reactions. We report that NAMPT, the rate-limiting enzyme of the salvage pathway of NAD synthesis, antagonizes tegument protein incorporation and restricts herpesvirus lytic replication in an enzyme-independent manner. We demonstrated that NAMPT was packaged into the virion and reduced lytic replication of human herpes simplex virus 1 (HSV-1). Mechanistically, NAMPT targets two core tegument proteins, UL36 and UL37 that mesh a scaffold for viral tegumentation during lytic replication. As such, NAMPT competitively antagonizes the incorporation of diverse tegument proteins into the virion, impairing viral tegumentation and infectivity of the progeny. Microscopy analysis indicates that NAMPT localizes to the TGN, which HSV-1 capsids bud into during tegumentation. Finally, NAMPT exhibited antiviral activity against multiple herpesviruses and loss of NAMPT rendered mice highly susceptible to HSV-1 infection. This study defines a new restriction factor targeting herpesvirus tegumentation, revealing a metabolism-independent antiviral activity of a metabolic enzyme.