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Kastner and colleagues review monogenic autoinflammatory diseases and their molecular mechanisms and explore the overlap among autoinflammation, autoimmunity and immunodeficiency. Autoinflammatory diseases were first recognized nearly 20 years ago as distinct clinical and immunological entities caused by dysregulation in the innate immune system. Since then, advances in genomic techniques have led to the identification of new monogenic disorders and their corresponding signaling pathways. Here we review these monogenic autoinflammatory diseases, ranging from periodic fever syndromes caused by dysregulated inflammasome-mediated production of the cytokine IL-1β to disorders arising from perturbations in signaling by the transcription factor NF-κB, ubiquitination, cytokine signaling, protein folding, type I interferon production and complement activation, and we further examine their molecular mechanisms. We also explore the overlap among autoinflammation, autoimmunity and immunodeficiency, and pose a series of unanswered questions that are expected to be central in autoinflammatory disease research in the coming decade.

Autophagy is an essential cellular process affecting virus infections and other diseases and Beclin1 (BECN1) is one of its key regulators. Here, we identified S-phase kinase-associated protein 2 (SKP2) as E3 ligase that executes lysine-48-linked poly-ubiquitination of BECN1, thus promoting its proteasomal degradation. SKP2 activity is regulated by phosphorylation in a hetero-complex involving FKBP51, PHLPP, AKT1, and BECN1. Genetic or pharmacological inhibition of SKP2 decreases BECN1 ubiquitination, decreases BECN1 degradation and enhances autophagic flux. Middle East respiratory syndrome coronavirus (MERS-CoV) multiplication results in reduced BECN1 levels and blocks the fusion of autophagosomes and lysosomes. Inhibitors of SKP2 not only enhance autophagy but also reduce the replication of MERS-CoV up to 28,000-fold. The SKP2-BECN1 link constitutes a promising target for host-directed antiviral drugs and possibly other autophagy-sensitive conditions. Here, Gassen et al . show that S-phase kinase-associated protein 2 (SKP2) is responsible for lysine-48-linked poly-ubiquitination of beclin 1, resulting in its proteasomal degradation, and that inhibition of SKP2 enhances autophagy and reduces replication of MERS coronavirus.

Key Points The tumour necrosis factor (TNF) and TNF receptor (TNFR) superfamilies comprise 19 ligands and 29 receptors, respectively. The signalling pathways induced by TNF engagement of TNFR1 — and, to a lesser extent, TNFR2 — are the primary focus of this review. TNF signalling through TNFR1 and TNFR2 leading to nuclear factor-κB (NF-κB) activation promotes cell survival. A hallmark of TNF-dependent NF-κB signalling is the complex regulation of receptor-interacting serine/threonine protein kinase 1 (RIPK1) activation through linear and branched ubiquitylation. RIPK1 ubiquitylation can be modulated by enzymes such as cellular inhibitor of apoptosis protein 1 (cIAP1), cIAP2, A20, Cezanne and cylindromatosis (CYLD). TNF-mediated signalling through non-ubiquitylated RIPK1 induces either apoptosis or necroptosis. Caspase activity is needed to induce TNF-dependent apoptosis and inactivate RIPK1 and RIPK3 by cleavage. Whereas the long isoform of FLICE-like inhibitory protein (FLIP L ) blocks apoptosis, the short isoform (FLIP S ) triggers necroptosis that depends on non-ubiquitylated RIPK1 and impaired caspase activity. RIPK3-dependent phosphorylation of mixed lineage kinase domain-like (MLKL) is essential for necroptosis but not apoptosis. TNF is involved in some autoimmune and inflammatory diseases, and therapeutic targeting of TNF has been successful for 20 years. However, TNF-specific therapies show little or no efficacy in other inflammatory disorders even when TNF apparently has a role in the pathology. New strategies for targeting TNF are currently being explored. In this Review, the authors describe how tumour necrosis factor (TNF) signals via its receptors. They explain how TNF is able to promote cell survival or cell death in different contexts and discuss the consequences of deregulated TNF receptor signalling for chronic human diseases. Finally, they discuss new strategies for targeting TNF in the clinic. Tumour necrosis factor (TNF) is a pro-inflammatory cytokine that has important roles in mammalian immunity and cellular homeostasis. Deregulation of TNF receptor (TNFR) signalling is associated with many inflammatory disorders, including various types of arthritis and inflammatory bowel disease, and targeting TNF has been an effective therapeutic strategy in these diseases. This Review focuses on the recent advances that have been made in understanding TNFR signalling and the consequences of its deregulation for cellular survival, apoptosis and regulated necrosis. We discuss how TNF-induced survival signals are distinguished from those that lead to cell death. Finally, we provide a brief overview of the role of TNF in inflammatory and autoimmune diseases, and we discuss up-to-date and future treatment strategies for these disorders.

Sensing cytosolic DNA through the cGAS–STING pathway constitutes a widespread innate immune mechanism to monitor cellular damage and microbial invasion. Evading this surveillance is crucial in tumorigenesis, but the process remains largely unexplored. Here, we show that the receptor tyrosine kinase HER2 (also known as ErbB-2 or Neu) potently inhibits cGAS–STING signalling and prevents cancer cells from producing cytokines, entering senescence and undergoing apoptosis. HER2, but not EGFR, associates strongly with STING and recruits AKT1 (also known as PKB) to directly phosphorylate TBK1, which prevents the TBK1–STING association and TBK1 K63-linked ubiquitination, thus attenuating STING signalling. Unexpectedly, we observed that DNA sensing robustly activates the HER2–AKT1 axis, resulting in negative feedback. Accordingly, genetic or pharmacological targeting of the HER2–AKT1 cascade augments damage-induced cellular senescence and apoptosis, and enhances STING-mediated antiviral and antitumour immunity. Thus, our findings reveal a critical function of the oncogenic pathway in innate immune regulation and unexpectedly connect HER2–AKT1 signalling to the surveillance of cellular damage and antitumour immunity. Wu et al. demonstrate that HER2 recruits AKT1 to disrupt the STING signalosome, thereby suppressing damage-induced cellular senescence and STING-mediated antiviral and antitumour responses in vivo.

Sun and colleagues show that the deubiquitinase USP15 stabilizes expression of the E3 ubiquitin ligase MDM2 in T cells, which results in inhibition of T cell activation, and in cancer cells, which results in survival of cancer cells. Deubiquitinases (DUBs) are a new class of drug targets, although the physiological function of only few DUBs has been characterized. Here we identified the DUB USP15 as a crucial negative regulator of T cell activation. USP15 stabilized the E3 ubiquitin ligase MDM2, which in turn negatively regulated T cell activation by targeting the degradation of the transcription factor NFATc2. USP15 deficiency promoted T cell activation in vitro and enhanced T cell responses to bacterial infection and tumor challenge in vivo . USP15 also stabilized MDM2 in cancer cells and regulated p53 function and cancer-cell survival. Our results suggest that inhibition of USP15 may both induce tumor cell apoptosis and boost antitumor T cell responses.

MAVS and MITA are essential adaptor proteins mediating innate antiviral immune responses against RNA and DNA viruses, respectively. Here we show that RNF115 plays dual roles in response to RNA or DNA virus infections by catalyzing distinct types of ubiquitination of MAVS and MITA at different phases of viral infection. RNF115 constitutively interacts with and induces K48-linked ubiquitination and proteasomal degradation of homeostatic MAVS in uninfected cells, whereas associates with and catalyzes K63-linked ubiquitination of MITA after HSV-1 infection. Consistently, the protein levels of MAVS are substantially increased in Rnf115 −/− organs or cells without viral infection, and HSV-1-induced aggregation of MITA is impaired in Rnf115 −/− cells compared to the wild-type counterparts. Consequently, the Rnf115 −/− mice exhibit hypo- and hyper-sensitivity to EMCV and HSV-1 infection, respectively. These findings highlight dual regulation of cellular antiviral responses by RNF115-mediated ubiquitination of MAVS and MITA and contribute to our understanding of innate immune signaling. MAVS and MITA are adapter proteins that play distinct roles in the context of the host response to RNA and DNA viruses, respectively. Here the authors implicate RNF115 in dual temporal and spatial mechanisms of interacting and catalyzing distinct ubiquitination of MAVS and MITA to modulate RNA and DNA antiviral immune responses.

In these studies, we evaluated the contribution of the NLRP3 inflammasome to Crohn's disease (CD) in a kindred containing individuals having a missense mutation in CARD8, a protein known to inhibit this inflammasome. Whole exome sequencing and PCR studies identified the affected individuals as having a V44I mutation in a single allele of the T60 isoform of CARD8. The serum levels of IL-1β in the affected individuals were increased compared with those in healthy controls, and their peripheral monocytes produced increased amounts of IL-1β when stimulated by NLRP3 activators. Immunoblot studies probing the basis of these findings showed that mutated T60 CARD8 failed to downregulate the NLRP3 inflammasome because it did not bind to NLRP3 and inhibit its oligomerization. In addition, these studies showed that mutated T60 CARD8 exerted a dominant-negative effect by its capacity to bind to and form oligomers with unmutated T60 or T48 CARD8 that impeded their binding to NLRP3. Finally, inflammasome activation studies revealed that intact but not mutated CARD8 prevented NLRP3 deubiquitination and serine dephosphorylation. CD due to a CARD8 mutation was not effectively treated by anti-TNF-α, but did respond to IL-1β inhibitors. Thus, patients with anti-TNF-α-resistant CD may respond to this treatment option.

For efficient replication, viruses have developed mechanisms to evade innate immune responses, including the antiviral type-I interferon (IFN-I) system. Nipah virus (NiV), a highly pathogenic member of the Paramyxoviridae family (genus Henipavirus), is known to encode for four P gene-derived viral proteins (P/C/W/V) with IFN-I antagonist functions. Here we report that NiV matrix protein (NiV-M), which is important for virus assembly and budding, can also inhibit IFN-I responses. IFN-I production requires activation of multiple signaling components including the IκB kinase epsilon (IKKε). We previously showed that the E3-ubiquitin ligase TRIM6 catalyzes the synthesis of unanchored K48-linked polyubiquitin chains, which are not covalently attached to any protein, and activate IKKε for induction of IFN-I mediated antiviral responses. Using co-immunoprecipitation assays and confocal microscopy we show here that the NiV-M protein interacts with TRIM6 and promotes TRIM6 degradation. Consequently, NiV-M expression results in reduced levels of unanchored K48-linked polyubiquitin chains associated with IKKε leading to impaired IKKε oligomerization, IKKε autophosphorylation and reduced IFN-mediated responses. This IFN antagonist function of NiV-M requires a conserved lysine residue (K258) in the bipartite nuclear localization signal that is found in divergent henipaviruses. Consistent with this, the matrix proteins of Ghana, Hendra and Cedar viruses were also able to inhibit IFNβ induction. Live NiV infection, but not a recombinant NiV lacking the M protein, reduced the levels of endogenous TRIM6 protein expression. To our knowledge, matrix proteins of paramyxoviruses have never been reported to be involved in innate immune antagonism. We report here a novel mechanism of viral innate immune evasion by targeting TRIM6, IKKε and unanchored polyubiquitin chains. These findings expand the universe of viral IFN antagonism strategies and provide a new potential target for development of therapeutic interventions against NiV infections.

Trafficking of toll-like receptor 3 (TLR3) from the endoplasmic reticulum (ER) to endolysosomes and its subsequent proteolytic cleavage are required for it to sense viral double-stranded RNA (dsRNA) and trigger antiviral response, yet the underlying mechanisms remain enigmatic. We show that the E3 ubiquitin ligase TRIM3 is mainly located in the Golgi apparatus and transported to the early endosomes upon stimulation with the dsRNA analog poly(I:C). TRIM3 mediates K63-linked polyubiquitination of TLR3 at K831, which is enhanced following poly(I:C) stimulation. The polyubiquitinated TLR3 is recognized and sorted by the ESCRT (endosomal sorting complex required for transport) complexes to endolysosomes. Deficiency of TRIM3 impairs TLR3 trafficking from the Golgi apparatus to endosomes and its subsequent activation. Trim3 −/− cells and mice express lower levels of antiviral genes and show lower levels of inflammatory response following poly(I:C) but not lipopolysaccharide (LPS) stimulation. These findings suggest that TRIM3-mediated polyubiquitination of TLR3 represents a feedback-positive regulatory mechanism for TLR3-mediated innate immune and inflammatory responses.