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Using metabolic dysfunction-associated steatohepatitis-driven hepatocellular carcinoma mouse models, an ATP citrate lyase inhibitor reduces tumour burden and enhances efficacy of current standards of care.

In this study, the authors isolated single-domain antibodies directed against conserved sites of influenza B virus neuraminidase and hemagglutinin and show that they broadly neutralize influenza B viruses and, as IgG Fc fusions, are protective in vivo.

Tsirigotaki et al. unveil how adipokine Leptin induces trimerization of the Leptin receptor to form a cytokine-receptor assembly critical to body weight regulation, immunity, fertility and cancer.

AtEH/Pan1 proteins contain two N-terminal Eps15 homology (EH) domains and are subunits of the endocytic TPLATE complex present in plants. Here, the authors combine X-ray crystallography, NMR and MD simulations with biochemical and in planta analysis to characterize the two AtEH1/Pan1 EH domains and reveal their structural differences and complementary functional roles.

Structural studies of the complex of anaplastic lymphoma kinase and leukocyte tyrosine kinase and their activating cytokines identify unique architectural features of the complex, and provide a novel mechanistic paradigm among receptor tyrosine kinases.

Protein scaffolds can serve as alternatives to antibodies in a range of applications. Here, the authors report the design and development of Alphabody™, a protein scaffold featuring a single-chain antiparallel triple-helix coiled-coil fold that the authors use to develop Alphabodies that can neutralize human IL-23 with high specificity and affinity.

Disrupting the association between the Immunoglobulin G constant fragment (Fc) and the neonatal Fc receptor (FcRn) by engineered antibodies is a promising strategy to reduce autoantibody levels in autoimmune diseases. Here authors show that the variable fragment (Fab) of immunoglobulins could disturb the Fc-FcRn interaction, therefore the therapeutic effect of Fc-only fragments might surpass that of Fc-engineered antibodies with enhanced binding to FcRn.

The pro-inflammatory cytokine thymic stromal lymphopoietin (TSLP) is a promising therapeutic target. Here the authors characterize the assembly mechanism of the receptor complex driven by human TSLP, and its antagonism by the monoclonal antibody Tezepelumab and a fusion protein comprising the TSLP receptors.

Viruses often subvert the host immune system using molecular decoys to prevent an effective immune response. Here, the authors examine the structural details of the viral decoy receptor GIF and its antagnosim of GM-CSF and IL-2.

The human colony-stimulating factor (hCSF-1) cytokine is essential for innate and adaptive immune responses. The Epstein-Barr virus protein BARF1 binds to hCSF-1, preventing interferon-α secretion. Structural and functional data reveal a new mechanism for the antagonism of human but not mouse CSF-1 signaling by BARF1.

Thymic stromal lymphopoietin (TSLP) is a cytokine critical for the development of chronic inflammatory disorders including asthma and atopic dermatitis. The structure of the ternary complex formed by TSLP and its coreceptors TSLPR and the interleukin-7 receptor reveal how TSLP is able to organize receptor-receptor contacts to facilitate intracellular signaling.

The proteins apoptosis regulator BAX (BAX), BCL-2 homologous antagonist/killer (BAK) and BCL-2-related ovarian killer protein (BOK), gasdermins and mixed lineage kinase domain-like protein (MLKL) are key executioners of regulated cell death by forming pores across the plasma or mitochondrial membrane. This Review discusses structural rearrangements during activation and oligomerization of these proteins and highlights commonalities and differences of pore formation mechanisms.

A design pipeline is presented whereby binding proteins can be designed de novo without the need for prior information on binding hotspots or fragments from structures of complexes with binding partners.

Newly discovered small-molecule TNF inhibitors serve as antagonists of pro-inflammatory TNF signalling by uniquely harnessing the conformational plasticity of trimeric TNF. The development of this approach could mark a resurgence of non-biologic modulators of clinically relevant protein–protein interactions in rheumatology.

Structures of complete extracellular receptor assemblies mediated by the pro-inflammatory cytokines IL-12 and IL-23 reveal key commonalities and diverse features, with only IL-12 juxtaposing receptor domains proximal to the cell membrane.

Recently, a pipeline for the design of protein-binding proteins using only the structure of the target protein was reported. Here, the authors report that the incorporation of deep learning methods into the original pipeline increases experimental success rate by ten-fold.

Intracellular signalling cascades initiated by class III receptor tyrosine kinases (RTK-IIIs) and their cytokine ligands are implicated in a wide range of inflammatory disorders and cancers. This Review discusses recent crystal structure data of RTK-III ectodomains in complex with cognate cytokines and the insights that these provide in terms of RTK-III activation, evolution, pathology and new therapeutic approaches.

Understanding how decoy receptors for cytokines and chemokines work requires in-depth insights into their structure. In this Review, the authors provide a structural overview of both mammalian and viral decoy receptors and highlight opportunities for leveraging their immunomodulatory activity for therapeutic purposes.

Determination of the high-resolution structure of yeast TORC1 allows characterization of the precise interfaces of interaction between inactive TORC1 and TORC1′ polymers and identification of the mode of binding of active EGOC on TORC1.

RIPK1 kinase activity is known to transduce a death signal, but the molecular mechanisms that normally prevent RIPK1 activation are unclear. Here, the authors report that IKK-mediated phosphorylation on RIPK1 Ser25 directly represses its enzymatic activity and thus RIPK1-dependent cell death.

Affinity-based target isolation and X-ray crystallography enabled identification of the non-protonophore ES9-17 as an inhibitor of the clathrin heavy chain in plants, enabling disruption of endocytosis.

Maintaining the intestinal barrier function requires a balance of multiple signalling pathways. Here the authors show that A20, an anti-inflammatory and anti-apoptotic protein, and Atg1611, an autophagy regulator, cross-regulate their respective protein levels and function to serve compensatory and redundant roles in fine-tuning gut barrier homeostasis.

Invariant natural killer T (iNKT) cells rapidly enhance cytokine secretion and effector function following activation, but the underlying mechanism is still unclear. Here the authors show that an endoplasmic reticulum stress sensor, inositol-requiring enzyme 1α, activates the p38 kinase to stabilize cytokine mRNA for enhanced iNKT functions.

The signaling receptor Notch is required for the generation of marginal zone B cells. Hammad and colleagues show that Notch signaling activates the kinase Taok3 and surface expression of the metalloproteinase ADAM10, which commits transitional B cells to the marginal zone B cell fate.

Crystal structures of ATP citrate lyase from bacteria, archaea and humans unravel how the enzyme directs the formation of the central metabolite acetyl-CoA, and shed light onto the evolutionary origins of the Krebs cycle.

Inhibition of CSF-1R with recurrent activating alterations and other actionable targets identified by genomic sequencing elicits clinical activity in patients with histiocytosis.