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Excessive inflammatory responses induced upon SARS-CoV-2 infection are associated with severe symptoms of COVID-19. Inflammasomes activated in response to SARS-CoV-2 infection are also associated with COVID-19 severity. Here, we show a distinct mechanism by which SARS-CoV-2 N protein promotes NLRP3 inflammasome activation to induce hyperinflammation. N protein facilitates maturation of proinflammatory cytokines and induces proinflammatory responses in cultured cells and mice. Mechanistically, N protein interacts directly with NLRP3 protein, promotes the binding of NLRP3 with ASC, and facilitates NLRP3 inflammasome assembly. More importantly, N protein aggravates lung injury, accelerates death in sepsis and acute inflammation mouse models, and promotes IL-1β and IL-6 activation in mice. Notably, N-induced lung injury and cytokine production are blocked by MCC950 (a specific inhibitor of NLRP3) and Ac-YVAD-cmk (an inhibitor of caspase-1). Therefore, this study reveals a distinct mechanism by which SARS-CoV-2 N protein promotes NLRP3 inflammasome activation and induces excessive inflammatory responses. SARS-CoV-2 infection has been shown to drive NLRP3 inflammasome activation and thereby cytokine storm, but how it does so is unclear. Here the authors show that the viral N protein can bind to NLRP3, resulting in enhanced interaction with ASC and thereby with the NLRP3 inflammasome.

Pattern-triggered immunity (PTI) and effector-triggered immunity (ETI) in plants enable them to respond to pathogens by activating the production of defence metabolites that orchestrate immune responses 1 – 4 . How the production of defence metabolites is promoted by immune receptors and coordinated with broad-spectrum resistance remains elusive. Here we identify the deubiquitinase PICI1 as an immunity hub for PTI and ETI in rice ( Oryza sativa ). PICI1 deubiquitinates and stabilizes methionine synthetases to activate methionine-mediated immunity principally through biosynthesis of the phytohormone ethylene. PICI1 is targeted for degradation by blast fungal effectors, including AvrPi9, to dampen PTI. Nucleotide-binding domain, leucine-rich-repeat-containing receptors (NLRs) in the plant immune system, such as PigmR, protect PICI1 from effector-mediated degradation to reboot the methionine–ethylene cascade. Natural variation in the PICI1 gene contributes to divergence in basal blast resistance between the rice subspecies indica and japonica . Thus, NLRs govern an arms race with effectors, using a competitive mode that hinges on a critical defence metabolic pathway to synchronize PTI with ETI and ensure broad-spectrum resistance. The deubiquitinase PICI1 is identified as part of an immunity hub that coordinates pattern- and effector-triggered immunity and is involved in conferring broad-spectrum resistance to blast across different subspecies of rice.

Ferroptosis is a lipid peroxidation-driven and iron-dependent programmed cell death involved in multiple physical processes and various diseases. Emerging evidence suggests that several pathogens manipulate ferroptosis for their pathogenicity and dissemination, but the underlying molecular mechanisms remain elusive. Here, we identify that protein tyrosine phosphatase A (PtpA), an effector secreted by tuberculosis (TB)-causing pathogen Mycobacterium tuberculosis (Mtb), triggers ferroptosis to promote Mtb pathogenicity and dissemination. Mechanistically, PtpA, through its Cys11 site, interacts with host RanGDP to enter host cell nucleus. Then, the nuclear PtpA enhances asymmetric dimethylation of histone H3 arginine 2 (H3R2me2a) via targeting protein arginine methyltransferase 6 (PRMT6), thus inhibiting glutathione peroxidase 4 (GPX4) expression, eventually inducing ferroptosis to promote Mtb pathogenicity and dissemination. Taken together, our findings provide insights into molecular mechanisms of pathogen-induced ferroptosis, indicating a potential TB treatment via blocking Mtb PtpA-host PRMT6 interface to target GPX4-dependent ferroptosis. Ferroptosis is an iron-dependent form of cell death whose role in infectious diseases is being elucidated. Here, Qiang et al. show that PtpA, an effector secreted by Mycobacterium tuberculosis , induces ferroptosis by hijacking host arginine methyltransferase PRMT6 to promote its pathogenicity and dissemination.

Technological and computational advances in genomics and interactomics have made it possible to identify how disease mutations perturb protein–protein interaction (PPI) networks within human cells. Here, we show that disease-associated germline variants are significantly enriched in sequences encoding PPI interfaces compared to variants identified in healthy participants from the projects 1000 Genomes and ExAC. Somatic missense mutations are also significantly enriched in PPI interfaces compared to noninterfaces in 10,861 tumor exomes. We computationally identified 470 putative oncoPPIs in a pan-cancer analysis and demonstrate that oncoPPIs are highly correlated with patient survival and drug resistance/sensitivity. We experimentally validate the network effects of 13 oncoPPIs using a systematic binary interaction assay, and also demonstrate the functional consequences of two of these on tumor cell growth. In summary, this human interactome network framework provides a powerful tool for prioritization of alleles with PPI-perturbing mutations to inform pathobiological mechanism- and genotype-based therapeutic discovery. Human disease mutations affect protein–protein interfaces in a three-dimensional structurally resolved interaction network. Predicted oncoPPIs in cancer correlate with survival and drug sensitivity, and affect growth in vitro, supporting their relevance to disease pathogenesis.

Plant hormones coordinate responses to environmental cues with developmental programs 1 , and are fundamental for stress resilience and agronomic yield 2 . The core signalling pathways underlying the effects of phytohormones have been elucidated by genetic screens and hypothesis-driven approaches, and extended by interactome studies of select pathways 3 . However, fundamental questions remain about how information from different pathways is integrated. Genetically, most phenotypes seem to be regulated by several hormones, but transcriptional profiling suggests that hormones trigger largely exclusive transcriptional programs 4 . We hypothesized that protein–protein interactions have an important role in phytohormone signal integration. Here, we experimentally generated a systems-level map of the Arabidopsis phytohormone signalling network, consisting of more than 2,000 binary protein–protein interactions. In the highly interconnected network, we identify pathway communities and hundreds of previously unknown pathway contacts that represent potential points of crosstalk. Functional validation of candidates in seven hormone pathways reveals new functions for 74% of tested proteins in 84% of candidate interactions, and indicates that a large majority of signalling proteins function pleiotropically in several pathways. Moreover, we identify several hundred largely small-molecule-dependent interactions of hormone receptors. Comparison with previous reports suggests that noncanonical and nontranscription-mediated receptor signalling is more common than hitherto appreciated. A systems-level map of the Arabidopsis hormone signalling network, comprising more than 2,000 binary protein–protein interactions, reveals hundreds of interpathway contact points, many of which mediate crosstalk between different hormone pathways.

Shapes of edible plant organs vary dramatically among and within crop plants. To explain and ultimately employ this variation towards crop improvement, we determined the genetic, molecular and cellular bases of fruit shape diversity in tomato. Through positional cloning, protein interaction studies, and genome editing, we report that OVATE Family Proteins and TONNEAU1 Recruiting Motif proteins regulate cell division patterns in ovary development to alter final fruit shape. The physical interactions between the members of these two families are necessary for dynamic relocalization of the protein complexes to different cellular compartments when expressed in tobacco leaf cells. Together with data from other domesticated crops and model plant species, the protein interaction studies provide possible mechanistic insights into the regulation of morphological variation in plants and a framework that may apply to organ growth in all plant species. Remarkable organ shape morphological diversity exists in fruits, vegetables and seeds. Here, the authors establish a link between OVATE Family Proteins and TONNEAU1 Recruiting Motif family proteins in the development pathway that governs fruit shape of tomato, melon, and cucumber as well as potato tuber shape.

Tree peony ( Paeonia ostii ) is an economically important ornamental plant native to China. It is also notable for its seed oil, which is abundant in unsaturated fatty acids such as α-linolenic acid (ALA). Here, we report chromosome-level genome assembly (12.28 Gb) of P. ostii . In contrast to monocots with giant genomes, tree peony does not appear to have undergone lineage-specific whole-genome duplication. Instead, explosive LTR expansion in the intergenic regions within a short period (~ two million years) may have contributed to the formation of its giga-genome. In addition, expansion of five types of histone encoding genes may have helped maintain the giga-chromosomes. Further, we conduct genome-wide association studies (GWAS) on 448 accessions and show expansion and high expression of several genes in the key nodes of fatty acid biosynthetic pathway, including SAD , FAD2 and FAD3 , may function in high level of ALAs synthesis in tree peony seeds. Moreover, by comparing with cultivated tree peony ( P. suffruticosa ), we show that ectopic expression of class A gene AP1 and reduced expression of class C gene AG may contribute to the formation of petaloid stamens. Genomic resources reported in this study will be valuable for studying chromosome/genome evolution and tree peony breeding. Tree peony ( Paeonia ostii ) has the largest chromosome of any sequenced plants to date. Here, the authors assemble its genome and reveal the association of a list of candidate genes with fatty acid biosynthesis and the possible contribution of transposon and histone expansion to maintain the giga-chromosomes.

Soybean ( Glycine max ) serves as a major source of protein and edible oils worldwide. The genetic and genomic bases of the adaptation of soybean to tropical regions remain largely unclear. Here, we identify the novel locus Time of Flowering 16 ( Tof16 ), which confers delay flowering and improve yield at low latitudes and determines that it harbors the soybean homolog of LATE ELONGATED HYPOCOTYL ( LHY ). Tof16 and the previously identified J locus genetically additively but independently control yield under short-day conditions. More than 80% accessions in low latitude harbor the mutations of tof16 and j , which suggests that loss of functions of Tof16 and J are the major genetic basis of soybean adaptation into tropics. We suggest that maturity and yield traits can be quantitatively improved by modulating the genetic complexity of various alleles of the LHY homologs, J and E1 . Our findings uncover the adaptation trajectory of soybean from its temperate origin to the tropics. How soybean, a temperate origin crop, adapted to a tropical environment remains unclear. Here, the authors report Tof16 , an ortholog of LHY , and the previously identified J locus, control soybean yield under short-day condition and loss of function of these two genes contributes to the adaptation to tropics.

Doris Wagner and colleagues define Polycomb response elements (PREs) that direct the placement of Polycomb repressive complex 2 (PRC2) at developmental genes in Arabidopsis . They identify transcription factor families that bind to PREs, physically interact with and recruit PRC2, and are required for gene silencing in vivo . Disruption of gene silencing by Polycomb protein complexes leads to homeotic transformations and altered developmental-phase identity in plants 1 , 2 , 3 , 4 , 5 . Here we define short genomic fragments, known as Polycomb response elements (PREs), that direct Polycomb repressive complex 2 (PRC2) placement at developmental genes regulated by silencing in Arabidopsis thaliana . We identify transcription factor families that bind to these PREs, colocalize with PRC2 on chromatin, physically interact with and recruit PRC2, and are required for PRC2-mediated gene silencing in vivo . Two of the cis sequence motifs enriched in the PREs are cognate binding sites for the identified transcription factors and are necessary and sufficient for PRE activity. Thus PRC2 recruitment in Arabidopsis relies in large part on binding of trans -acting factors to cis -localized DNA sequence motifs.

The occurrence of whole-genome duplication or polyploidy may promote plant adaptability to harsh environments. Here, we clarify the evolutionary relationship of eight GhCIPK6 homologous genes in upland cotton ( Gossypium hirsutum ). Gene expression and interaction analyses indicate that GhCIPK6 homologous genes show significant functional changes after polyploidy. Among these, GhCIPK6D1 and GhCIPK6D3 are significantly up-regulated by drought stress. Functional studies reveal that high GhCIPK6D1 expression promotes cotton drought sensitivity, while GhCIPK6D3 expression promotes drought tolerance, indicating clear functional differentiation. Genetic and biochemical analyses confirm the synergistic negative and positive regulation of cotton drought resistance through GhCBL1A1-GhCIPK6D1 and GhCBL2A1-GhCIPK6D3, respectively, to regulate stomatal movement by controlling the directional flow of K + in guard cells. These results reveal differentiated roles of GhCIPK6 homologous genes in response to drought stress in upland cotton following polyploidy. The work provides a different perspective for exploring the functionalization and subfunctionalization of duplicated genes in response to polyploidization. Functional differentiation of homologous genes are usually followed by polyploidization in plants, which may contribute to adaptation. Here, the authors report the negative and positive synergistic regulation of GhCBL1A1-GhCIPK6D1 and GhCBL2A1-GhCIPK6D3, respectively, on drought resistance in cotton.