Wheat zinc finger protein TaZF interacts with both the powdery mildew AvrPm2 protein and the corresponding wheat Pm2a immune receptor

Plant defense responses to pathogens are induced after direct or indirect perception of effector proteins or their activity on host proteins.In fungal–plant interactions,relatively little is known about whether,in addi-tion to avirulence effectors and immune receptors,other proteins contribute to specific recognition.The nucleotide-binding leucine-rich repeat(NLR)immune receptor Pm2a in wheat recognizes the fungal pow-dery mildew effector AvrPm2.We found that the predicted wheat zincfinger TaZF interacts with both the fungal avirulence protein AvrPm2 and the wheat NLR Pm2a.We further demonstrated that the virulent AvrPm2-H2 variant does not interact with TaZF.TaZF silencing in wheat resulted in a reduction but not a loss of Pm2a-mediated powdery mildew resistance.Interaction studies showed that the leucine-rich repeat domain of Pm2a is the mediator of the interaction with TaZF.TaZF recruits both Pm2a and AvrPm2 from the cytosol to the nucleus,resulting in nuclear localization of Pm2a,TaZF,and AvrPm2 in wheat.We propose that TaZF acts as a facilitator of Pm2a-dependent AvrPm2 effector recognition.Ourfindings highlight the importance of identifying effector host targets for characterization of NLR-mediated effector recognition.

An XA21-Associated Kinase （OsSERK2） Regulates Immunity Mediated by the XA21 and XA3 Immune Receptors

The rice XA21 immune receptor kinase and the structurally related XA3 receptor confer immunity to Xanthomonas oryzae pv. oryzae （Xoo）, the causal agent of bacterial leaf blight. Here we report the isolation of OsSERK2 （rice somatic embryogenesis receptor kinase 2） and demonstrate that OsSERK2 positively regulates immunity mediated by XA21 and XA3 as well as the rice immune receptor FLS2 （OsFLS2）. Rice plants silenced for OsSerk2 display altered morphology and reduced sensitivity to the hormone brassinolide. OsSERK2 interacts with the intracellular domains of each immune receptor in the yeast two-hybrid system in a kinase activity-dependent manner. OsSERK2 undergoes bidi- rectional transphosphorylation with XA21 in vitro and forms a constitutive complex with XA21 in vivo. These results demonstrate an essential role for OsSERK2 in the function of three rice immune receptors and suggest that direct interaction with the rice immune receptors is critical for their function. Taken together, our findings suggest that the mechanism of OsSERK2-meditated regulation of rice XA21, XA3, and FLS2 differs from that of AtSERK3/BAK1-mediated regulation of Arabidopsis FLS2 and EFR.

Molecular actions of NLR immune receptors in plants and animals

NLRs constitute intracellular immune receptors in both plants and animals. Direct or indirect ligand recognition results in formation of oligomeric NLR complexes to mediate immune signaling. Over the past 20 years, rapid progress has been made in our understanding of NLR signaling. Structural and biochemical studies provide insight into molecular basis of autoinhibition,ligand recognition, and resistosome/inflammasome formation of several NLRs. In this review, we summarize these studies focusing on the structural aspect of NLRs. We also discuss the analogies and differences between plant and animal NLRs in their mechanisms of action and how the available knowledge may shed light on the signaling mechanisms of other NLRs.

Neuronal Fc gamma receptor I as a novel mediator for IgG immune complex-induced peripheral sensitization

Chronic pain often accompanies immune-related diseases with an elevated level of IgG immune complex （IgG-IC） in the serum and/or the affected tissues though the underlying mechanisms are largely unknown. Fc gamma receptors （FcyRs）, known as the receptors for the Fc domain of immunoglobulin G （IgG）, are typically expressed on immune cells. A general consensus is that the activation of FcyRs by IgG-IC in such immune cells induces the release of proinflammatory cytokines from the immune cells, which may contribute to the IgG-IC-mediated peripheral sensitization. In addition to the immune cells, recent studies have revealed that FcyRI, but not FcyRII and FcyRIII, is also expressed in a subpopulation of primary sensory neurons. Moreover, IgG-IC directly excites the primary sensory neurons through neuronal FcyRI. These findings indicate that neuronal FcyRI provides a novel direct linkage between immunoglobulin and primary sensory neurons, which may be a novel target for the treatment of pain in the immune-related disorders. In this review, we summarize the expression pattern, functions, and the associated cellular signaling of FcyRs in the primary sensory neurons.

Prediction of Tumor Microenvironment Characteristics and Treatment Response in Lung Squamous Cell Carcinoma by Pseudogene OR7E47P-related Immune Genes

Objective Pseudogenes are initially regarded as nonfunctional genomic sequences,but some pseudogenes regulate tumor initiation and progression by interacting with other genes to modulate their transcriptional activities.Olfactory receptor family 7 subfamily E member 47 pseudogene(OR7E47P)is expressed broadly in lung tissues and has been identified as a positive regulator in the tumor microenvironment(TME)of lung adenocarcinoma(LUAD).This study aimed to elucidate the correlation between OR7E47P and tumor immunity in lung squamous cell carcinoma(LUSC).Methods Clinical and molecular information from The Cancer Genome Atlas(TCGA)LUSC cohort was used to identify OR7E47P-related immune genes(ORIGs)by weighted gene correlation network analysis(WGCNA).Based on the ORIGs,2 OR7E47P clusters were identified using non-negative matrix factorization(NMF)clustering,and the stability of the clustering was tested by an extreme gradient boosting classifier(XGBoost).LASSO-Cox and stepwise regressions were applied to further select prognostic ORIGs and to construct a predictive model(ORPScore)for immunotherapy.The Botling cohorts and 8 immunotherapy cohorts(the Samstein,Braun,Jung,Gide,IMvigor210,Lauss,Van Allen,and Cho cohorts)were included as independent validation cohorts.Results OR7E47P expression was positively correlated with immune cell infiltration and enrichment of immune-related pathways in LUSC.A total of 57 ORIGs were identified to classify the patients into 2 OR7E47P clusters(Cluster 1 and Cluster 2)with distinct immune,mutation,and stromal programs.Compared to Cluster 1,Cluster 2 had more infiltration by immune and stromal cells,lower mutation rates of driver genes,and higher expression of immune-related proteins.The clustering performed well in the internal and 5 external validation cohorts.Based on the 7 ORIGs(HOPX,STX2,WFS,DUSP22,SLFN13,GGCT,and CCSER2),the ORPScore was constructed to predict the prognosis and the treatment response.In addition,the ORPScore was a better prognostic factor and correlated positively with the immunotherapeutic response in cancer patients.The area under the curve values ranged from 0.584 to 0.805 in the 6 independent immunotherapy cohorts.Conclusion Our study suggests a significant correlation between OR7E47P and TME modulation in LUSC.ORIGs can be applied to molecularly stratify patients,and the ORPScore may serve as a biomarker for clinical decision-making regarding individualized prognostication and immunotherapy.

Advances in oxidative stress and NOD-like/toll-like receptors in acute renal injury

Acute Kidney Injury(AKI)is a clinical syndrome characterized by rapid renal deterioration with high morbidity and mortality.Renal reperfusion(IRI),renal toxicity and sepsis are the main causes of AKI.IRI is one of the main causes of acute kidney injury in clinic,accounting for 75%of all the causes of AKI[1].The fatality rate of AKI caused by IRI is high,and the surviving patients may leave chronic renal impairment with different degrees[2].A number of studies have shown that ischemia-reperfusion injury leading to renal dysfunction is directly related to oxidative stress,and the inhibition of oxidative stress through nod-like/toll-like signaling pathway can reduce acute renal injury.This review summarizes the research progress in regulating oxidative stress and the relationship between innate immune receptors and acute renal injury.

Helicobacter pylori-associated immune thrombocytopenia:Clinical features and pathogenic mechanisms

Immune thrombocytopenia (ITP) is an autoimmune disease mediated by anti-platelet autoantibodies. There is growing evidence that the eradication of Helicobacter pylori (H. pylori) effectively increases platelet count in a considerable proportion of ITP patients infected with this bacterium. In the majority of ITP patients responding to H. pylori eradication therapy, the anti-platelet autoantibody response is completely resolved with no relapse for more than 7 years, indicating that the disease is cured. Therefore, adult patients with suspected ITP should be examined for H. pylori infection, and eradication therapy is recommended if the infection is present. Notably, however, the efficacy of H. pylori eradication therapy in ITP patients varies widely among countries, with a higher response rate in Japan compared with the United States and European countries other than Italy. The pathogenesis of H. pylori-associated ITP is still uncertain, although the mechanisms are known to involve multiple factors. H. pylori may modulate the Fcγ-receptor balance of monocytes/macrophages in favor of activating Fcγ receptors, and H. pylori components may mimic the molecular makeup of platelet antigens. Further studies of the pathogenic process of H. pylori-associated ITP may be useful for the development of new therapeutic strategies for ITP.

TIR enzymatic functions:signaling molecules and receptor mechanisms

The evolutionarily conserved Toll/Interleukin-1 Receptor(TIR)domains across kingdoms of prokaryotes,plants,and animals play critical roles in innate immunity.Recent studies have revealed the enzymatic functions of TIRs,the structural bases of TIRs as holoenzymes,and the identity of TIR-generated small signaling molecules and their receptors,which significantly advanced our understanding on TIR-mediated immune signaling pathways.We reviewed the most up-to-date findings in TIR enzymatic functions from the perspectives of signaling molecules and receptor mechanisms.

From molecule to cell:the expanding frontiers of plant immunity

In recent years,the field of plant immunity has witnessed remarkable breakthroughs.During the co-evolution between plants and pathogens,plants have developed a wealth of intricate defense mechanisms to safeguard their survival.Newly identified immune receptors have added unexpected complexity to the surface and intracellular sensor networks,enriching our understanding of the ongoing plant–pathogen interplay.Deciphering the molecular mechanisms of resistosome shapes our understanding of these mysterious molecules in plant immunity.Moreover,technological innovations are expanding the horizon of the plant–pathogen battlefield into spatial and temporal scales.While the development provides new opportunities for untangling the complex realm of plant immunity,challenges remain in uncovering plant immunity across spatiotemporal dimensions from both molecular and cellular levels.

Research on ADR1s helps understanding the plant immune network

Plant innate immunity begins with the recognition of pathogens by plasma membrane localized pattern-recognition receptors(PRRs)and intracellular nucleotide-binding domain leucine-rich repeat containing receptors(NLRs),which lead to pattern-triggered immunity(PTI)and effector-triggered immunity(ETI),respectively.For a long time,PTI and ETI have been regarded as two independent processes although they share multiple components and signal outputs.Increasing evidence shows an intimate link between PTI and ETI.PTI and ETI mutually potentiate each other,and this is essential for robust disease resistance during pathogen infection.An ancient class of NLRs called RNLs,so named because they carry a Resistance to Powdery Mildew 8(RPW8)-like coiled-coil(CC)domain in the N terminus,has emerged as a key node connecting PTI and ETI.RNLs not only act as helper NLRs that signal downstream of sensor NLRs,they also directly mediate PTI signaling by associating with PRR complexes.Here,we focus on Activated Disease Resistance 1(ADR1),a subclass of RNLs,and discuss its role and mechanism in plant immunity.

Exposure to heat-inactivated Trichophyton rubrum resulting in a limited immune response of human keratinocytes

Background Trichophyton rubrum （T. rubrum） represents the most important agent of dermatophytosis in humans. T. rubrum infection causes slight inflammation, and tends to be chronic and recurrent. It is suggested that it may result from the failure of epithelial cells to recognize T. rubrum effectively and initiate effective immune responses. The C-type lectin receptors （CLR） and toll-like receptors （TLR） are the two major pattern recognition receptors （PRRs） that recognize fungal components. Therefore, the purpose of the study was to analyze the expression of those PRRs and the cytokines in HaCaT cells stimulated with heat-inactivated T. rubrum conidia and hyphae, respectively. Methods HaCaT cells were unstimulated or stimulated with heat-inactivated T. rubrum conidia and hyphae （l×106 and 1.5×105 colony-forming unit （CFU） in 2 ml medium, respectively） for 6, 12 and 24 hours. The mRNA expression of PRRs involved in recognizing fungal pathogen-associated molecular patterns （PAMPs） and signaling molecules were measured by quantitative reverse transcription polymerase chain reaction （RT-PCR）. Meanwhile, surface toll-like receptor （TLR） 2, TLR4 and Dectin-1 were analyzed by fluorescence-activated cell sorter （FACS） 24 hours after treatment. The cytokines were detected in cell culture supernatants of HaCaT cells in 12 and 24 hours after treatment. Results HaCaT cells constitutively expressed mRNA of membrane-bound TLR1,2, 4 and 6, Dectinl and DC-SIGN, but not Dectin-2 or Mincle. Heat-killed T. rubrum did not significantly upregulate gene transcriptions of the PRRs of HaCaT cells. Heat-inactivated T. rubrum conidia significantly reduced the surface expression of TLR2 and Dectin-1, and suppressed the secretions of interferon-inducible protein-10 （IP-10） and monocyte chemotactic protein-1 （MCP-1） of HaCaT cells, while heat-killed T. rubrum hyphae significantly induced the secretions of IP-10 and MCP-I. Conclusion The cell-wall antigens of T. rubrum fail to activate transcriptional expression of PRRs and induce a lower immune response of HaCaT cells by limited cytokines secretion.

NADase and now Ca^(2+) channel, what else to learn about plant NLRs?

Plant intracellular immune receptors known as NLR(Nucleotide-binding Leucine-rich repeat,NB-LRR)proteins confer resistance and cause cell death upon recognition of cognate effector proteins from pathogens.Plant NLRs contain a variable N-terminal domain:a Toll/interleukin-1 receptor(TIR)domain or a coiled-coil(CC)domain or an RPW8(Resistance to Powdery Mildew 8)-like CC(CCR)domain.TIR-NLR,CC-NLR and CCR-NLR are known as TNL,CNL and RNL,respectively.TNLs and CNLs recognize pathogen effectors to activate cell death and defense responses,thus are regarded as sensor NLRs.RNLs are required downstream of TNLs to activate cell death and defense responses,thus are regarded as helper NLRs.Previous studies show that some TNLs form tetrameric resistosome as NAD+cleaving enzymes to transduce signal,while some CNLs form pentameric resistosome with undefined biochemical function.Two recent breakthrough studies show that activated CNL and RNL function as Ca2+channel to cause cell death and defense responses and provide a completely new insight into the downstream signaling events of CNL and TNL pathways.

Expression of Innate Immunity Genes in Epithelial Cells of Hypertrophic Adenoids with and without Pediatric Chronic Rhinosinusitis： A Preliminary Report

Background： Adenoid hypertrophy （AH） is associated with pediatric chronic rhinosinusitis （pCRS）, but its role in the inflammatory process of pCRS is unclear. It is thought that innate immunity gene expression is disrupted in the epithelium of patients with chronic rhinosinusitis （CRS）, including antimicrobial peptides and pattern recognition receptors （PRRs）. The aim of this preliminary study was to detect the expression of innate immunity genes in epithelial cells of hypertrophic adenoids with and without pCRS to better understand their role in pCRS. Methods： Nine pCRS patients and nine simple AH patients undergoing adenoidectomy were recruited for the study. Adenoidal epithelium was isolated, and real-time quantitative polymerase chain reaction （RT-qPCR） was employed to measure relative expression levels of the following messenger RNAs in hypertrophic adenoid epithelial cells of pediatric patients with and without CRS： Human β-defensin （HBD） 2 and 3, surfactant protein （SP）-A and D, toll-like receptors 1-10, nucleotide-binding oligomerization domain （NOD）-like receptors NOD 1, NOD 2, and NACHT, LRR and PYD domains-containing protein 3, retinoic acid-induced gene 1, melanoma differentiation-associated gene 5, and nuclear factor-riB （NF-KB）. RT-qPCR data from two groups were analyzed by independent sample t-tests and Mann-Whitney U-tests. Results： The relative expression of SP-D in adenoidal epithelium ofpCRS group was significantly lower than that in AH group （pCRS 0.73 ± 0.10 vs. AH 1.21 ±0.15; P = 0.0173, t = 2.654）. The relative expression levels of all tested PRRs and NF-κB, as well as HBD-2, HBD-3, and SP-A, showed no statistically significant differences in isolated adenoidal epithelium between pCRS group and AH group. Conclusions： Down-regulated SP-D levels in adenoidal epithelium may contribute to the development of pCRS. PRRs, however, are unlikely to play a significant role in the inflammatory process ofpCRS.

Human cancergermlineantigen-specific cytotoxicTcell-what canwelearnfrompatient

In this review,we will highlight the importance of cancer germline antigen-specific cytotoxic CD8^(+) T lymphocytes(CTL)and the factors affecting antitumor CTL responses.In light of cancer immunotherapy,we will emphasis the need to further understand the features,characteristics,and actions of modulatory receptors of human cancer germline-specific CTLs,in order to determine the optimal conditions for antitumor CTL responses.

Proxitome profiling reveals a conserved SGT1-NSL1 signaling module that activates NLR-mediated immunity

Suppressor of G2 allele of skp1(SGT1)is a highly conserved eukaryotic protein that plays a vital role in growth,development,and immunity in both animals and plants.Although some SGT1 interactors have been identified,the molecular regulatory network of SGT1 remains unclear.SGT1 serves as a co-chaperone to stabilize protein complexes such as the nucleotide-binding leucine-rich repeat(NLR)class of immune receptors,thereby positively regulating plant immunity.SGT1 has also been found to be asso-ciated with the SKP1-Cullin-F-box(SCF)E3 ubiquitin ligase complex.However,whether SGT1 targets im-mune repressors to coordinate plant immune activation remains elusive.In this study,we constructed a toolbox for TurbolD-and split-TurbolD-based proximity labeling(PL)assays in Nicotiana benthamiana and used the PL toolbox to explore the SGT1 interactome during pre-and post-immune activation.The comprehensive SGT1 interactome network we identified highlights a dynamic shift from proteins associ-ated with plant development to those linked with plant immune responses.We found that SGT1 interacts with Necrotic Spotted Lesion1(NSL1),which negatively regulates salicylic acid-mediated defenseby inter-fering with the nucleocytoplasmic trafficking of non-expressor of pathogenesis-related genes 1(NPR1)during N NLR-mediated response to tobacco mosaic virus.SGT1 promotes the SCF-dependent degrada-tion of NSL1 to facilitate immune activation,while salicylate-induced protein kinase-mediated phosphory-lation of SGT1further potentiates this process.Besides NNLR,NSL1also functions in several other NLR-mediated immunity.Collectively,our study unveils the regulatory landscape of SGT1 and reveals a novel SGT1-NSL1 signaling module that orchestrates plant innate immunity.