To investigate whether the cyclic AMP-responsive element modulator α (CREMα) polymorphisms are novel susceptibility factors for systemic lupus erythematosus (SLE), four tag SNPs, rs1057108, rs2295415, rs11592925, and rs1148247, were genotyped in 889 SLE cases and 825 healthy controls. Association analyses were performed on whole dataset or clinical/serologic subsets. Association statistics were calculated by age and sex adjusted logistic regression. The G allele frequencies of rs2295415 and rs1057108 were increased in SLE patients, compared with healthy controls (rs2295415: 21.2% versus 17.8%, OR 1.244, P = 0.019; rs1057108: 30.8% versus 27.7%, OR 1.165, P = 0.049). The haplotype constituted by the two risk alleles "G-G" from rs1057108 and rs2295415 displayed strong association with SLE susceptibility (OR 1.454, P = 0.00056). Following stratification by clinical/serologic features, a suggestive association was observed between rs2295415 and anti-Sm antibodies-positive SLE (OR 1.382, P = 0.044). Interestingly, a potential protective effect of rs2295415 was observed for SLE patients with renal disorder (OR 0.745, P = 0.032). Our data provide first evidence that CREMα SNPs rs2295415 and rs1057108 maybe novel genetic susceptibility factors for SLE. SNP rs2295415 appears to confer higher risk to develop anti-Sm antibodies-positive SLE and may play a protective role against lupus nephritis.

Although rare variant C1Q deficiency was identified as causative risk for systemic lupus erythematosus (SLE), there are limited and inconsistent reports regarding the common polymorphisms of C1Q genes in SLE susceptibility. Furthermore, there are no reports concerning polymorphisms of C1S, C1R, and C1RL and whether they confer susceptibility to SLE. We therefore evaluated 22 SNPs across six C1-complex genes in two independent case-control cohorts, and identified four novel SNPs that confer protection from SLE. The four SNPs are all located in C1Q. Particularly, the variant rs653286 displayed an independent reduced risk on SLE susceptibility (OR 0.75, P = 2.16 × 10-3) and anti-dsDNA antibodies (OR 0.68, P = 0.024). By bioinformatics analysis, SNPs rs653286 and rs291985 displayed striking cis-eQTL effects on C1Q genes expression. Individuals homozygous for the 'protective' allele at four SNPs had significantly higher levels of serum C1q (rs680123-rs682658: P = 0.0022; rs653286-rs291985: P = 0.0076). To our knowledge, this is the first study to demonstrate that only C1Q polymorphisms are associated with SLE. The C1Q SNP rs653286 confers an independent protective effect on SLE susceptibility and affects transcript abundance.

Interleukin (IL)-33 is a proinflammatory cytokine contributing to the pathogenesis of rheumatoid arthritis (RA). The gene encoding IL-33 may serve as a genetic factor and be associated with the risk of RA. To investigate the potential association between IL33 and RA, we performed a case-control study based on Chinese Han population.

The bromodomain and extraterminal (BET) family of proteins comprises four members-BRD2, BRD3, BRD4 and the testis-specific isoform BRDT-that largely function as transcriptional coactivators and play critical roles in various cellular processes, including the cell cycle, apoptosis, migration and invasion. BET proteins enhance the oncogenic functions of major cancer drivers by elevating the expression of these drivers, such as c-Myc in leukemia, or by promoting the transcriptional activities of oncogenic factors, such as AR and ERG in prostate cancer. Pathologically, BET proteins are frequently overexpressed and are clinically linked to various types of human cancer; they are therefore being pursued as attractive therapeutic targets for selective inhibition in patients with cancer. To this end, a number of bromodomain inhibitors, including JQ1 and I-BET, have been developed and have shown promising outcomes in early clinical trials. Although resistance to BET inhibitors has been documented in preclinical models, the molecular mechanisms underlying acquired resistance are largely unknown. Here we report that cullin-3SPOP earmarks BET proteins, including BRD2, BRD3 and BRD4, for ubiquitination-mediated degradation. Pathologically, prostate cancer-associated SPOP mutants fail to interact with and promote the degradation of BET proteins, leading to their elevated abundance in SPOP-mutant prostate cancer. As a result, prostate cancer cell lines and organoids derived from individuals harboring SPOP mutations are more resistant to BET-inhibitor-induced cell growth arrest and apoptosis. Therefore, our results elucidate the tumor-suppressor role of SPOP in prostate cancer in which it acts as a negative regulator of BET protein stability and also provide a molecular mechanism for resistance to BET inhibitors in individuals with prostate cancer bearing SPOP mutations.

Seed germination and innate immunity both have significant effects on plant life spans because they control the plant's entry into the ecosystem and provide defenses against various external stresses, respectively. Much ecological evidence has shown that seeds with high vigor are generally more tolerant of various environmental stimuli in the field than those with low vigor. However, there is little genetic evidence linking germination and immunity in plants. Here, we show that the rice lectin receptor-like kinase OslecRK contributes to both seed germination and plant innate immunity. We demonstrate that knocking down the OslecRK gene depresses the expression of α-amylase genes, reducing seed viability and thereby decreasing the rate of seed germination. Moreover, it also inhibits the expression of defense genes, and so reduces the resistance of rice plants to fungal and bacterial pathogens as well as herbivorous insects. Yeast two-hybrid and co-immunoprecipitation experiments revealed that OslecRK interacts with an actin-depolymerizing factor (ADF) in vivo via its kinase domain. Moreover, the rice adf mutant exhibited a reduced seed germination rate due to the suppression of α-amylase gene expression. This mutant also exhibited depressed immune responses and reduced resistance to biotic stresses. Our results thus provide direct genetic evidence for a common physiological pathway connecting germination and immunity in plants. They also partially explain the common observation that high-vigor seeds often perform well in the field. The dual effects of OslecRK may be indicative of progressive adaptive evolution in rice.

Treatments that target immune checkpoints, such as the one mediated by programmed cell death protein 1 (PD-1) and its ligand PD-L1, have been approved for treating human cancers with durable clinical benefit. However, many patients with cancer fail to respond to compounds that target the PD-1 and PD-L1 interaction, and the underlying mechanism(s) is not well understood. Recent studies revealed that response to PD-1-PD-L1 blockade might correlate with PD-L1 expression levels in tumour cells. Hence, it is important to understand the mechanistic pathways that control PD-L1 protein expression and stability, which can offer a molecular basis to improve the clinical response rate and efficacy of PD-1-PD-L1 blockade in patients with cancer. Here we show that PD-L1 protein abundance is regulated by cyclin D-CDK4 and the cullin 3-SPOP E3 ligase via proteasome-mediated degradation. Inhibition of CDK4 and CDK6 (hereafter CDK4/6) in vivo increases PD-L1 protein levels by impeding cyclin D-CDK4-mediated phosphorylation of speckle-type POZ protein (SPOP) and thereby promoting SPOP degradation by the anaphase-promoting complex activator FZR1. Loss-of-function mutations in SPOP compromise ubiquitination-mediated PD-L1 degradation, leading to increased PD-L1 levels and reduced numbers of tumour-infiltrating lymphocytes in mouse tumours and in primary human prostate cancer specimens. Notably, combining CDK4/6 inhibitor treatment with anti-PD-1 immunotherapy enhances tumour regression and markedly improves overall survival rates in mouse tumour models. Our study uncovers a novel molecular mechanism for regulating PD-L1 protein stability by a cell cycle kinase and reveals the potential for using combination treatment with CDK4/6 inhibitors and PD-1-PD-L1 immune checkpoint blockade to enhance therapeutic efficacy for human cancers.

Rheumatoid arthritis (RA) is a progressive autoimmune disease affecting the joints. In this study, we investigated the role of the pro-angiogenic factor leptin in regulating reactive oxygen species (ROS) to promote cell migration and angiogenesis in RA. We showed that leptin triggered RA fibroblast-like synoviocyte (FLS) migration by increased ROS expression. Additionally, leptin enhanced human umbilical vein endothelial cell (HUVEC) tube formation in a ROS/hypoxia-inducible factor-1α-dependent manner, accompanied by increased production of vascular endothelial growth factor and interleukin (IL)-6. We also revealed that antagonists of tumor necrosis factor, IL-6 and IL-1β down-regulated ROS production of RA FLS induced by leptin, which subsequently attenuated RA FLS migration and HUVEC tube formation. These findings demonstrated that leptin might play an important role in RA FLS migration and HUVEC angiogenesis.

The brown plant hopper (BPH), Nilaparvata lugens, is one of the major pest of rice (Oryza sativa). Plant defenses against insect herbivores have been extensively studied, but our understanding of insect responses to host plants' resistance mechanisms is still limited. The purpose of this study is to characterize transcripts of BPH and reveal the responses of BPH insects to resistant rice at transcription level by using the advanced molecular techniques, the next-generation sequencing (NGS) and the single-molecule, real-time (SMRT) sequencing.

Osteosarcoma is the most common type of bone malignancy, and the pathogenesis has not been entirely elucidated yet. An important deimination modification enzyme PADI4 (peptidylarginine deiminase 4) has attracted much attention in recent years for its important function in several kinds of human tumors. However, the role of PADI4 on osteosarcoma tumorigenesis remains largely unrevealed. Here, we first assessed the effect of PADI4 on osteosarcoma proliferation by the CCK8 method and colony formation assay. Ectopically expressing PADI4 positively regulates the colony formation capacity of both U2OS and Saos-2 cells. Furthermore, we explored the related mechanism and showed that PADI4 could stimulate Wnt/β-catenin and MEK/ERK signaling in both U2OS and Saos-2 cells. Then, we detected expression of PADI4 in human tissues of osteosarcoma and revealed that differential expression of PADI4 was associated with tumorigenesis of osteosarcoma. Last, we performed the in vivo experiment in nude mice and results also showed PADI4 could affect the tumor growth. In conclusion, this work revealed that PADI4 could upregulate the proliferation of osteosarcoma, mainly via the Wnt/β-catenin and MEK/ERK signaling pathway. This study gives us new insight into the regulation mechanism of osteosarcoma proliferation and highlights PADI4 as a promising target for osteosarcoma diagnosis and treatment.

Plants deploy receptor-like kinases and nucleotide-binding leucine-rich repeat receptors to confer host plant resistance (HPR) to herbivores1. These gene-for-gene interactions between insects and their hosts have been proposed for more than 50 years2. However, the molecular and cellular mechanisms that underlie HPR have been elusive, as the identity and sensing mechanisms of insect avirulence effectors have remained unknown. Here we identify an insect salivary protein perceived by a plant immune receptor. The BPH14-interacting salivary protein (BISP) from the brown planthopper (Nilaparvata lugens Stål) is secreted into rice (Oryza sativa) during feeding. In susceptible plants, BISP targets O. satvia RLCK185 (OsRLCK185; hereafter Os is used to denote O. satvia-related proteins or genes) to suppress basal defences. In resistant plants, the nucleotide-binding leucine-rich repeat receptor BPH14 directly binds BISP to activate HPR. Constitutive activation of Bph14-mediated immunity is detrimental to plant growth and productivity. The fine-tuning of Bph14-mediated HPR is achieved through direct binding of BISP and BPH14 to the selective autophagy cargo receptor OsNBR1, which delivers BISP to OsATG8 for degradation. Autophagy therefore controls BISP levels. In Bph14 plants, autophagy restores cellular homeostasis by downregulating HPR when feeding by brown planthoppers ceases. We identify an insect saliva protein sensed by a plant immune receptor and discover a three-way interaction system that offers opportunities for developing high-yield, insect-resistant crops.

Recent evidence emphasized the role of the microbiota in the etiopathogenesis of rheumatoid arthritis (RA). Indeed, it has been demonstrated that urinary tract infections are implicated in RA pathogenesis. However, a definitive association between the urinary tract microbiota and RA remains to be investigated. Urine samples from 39 patients affected by RA, including treatment-naive patients, and 37 age- and sex-matched healthy individuals were collected. In RA patients, the urinary microbiota showed an increase in microbial richness and a decrease in microbial dissimilarity, especially in treatment-naive patients. A total of 48 altered genera with different absolute quantities were detected in patients with RA. The 37 enriched genera included Proteus, Faecalibacterium, and Bacteroides, while the 11 deficient genera included Gardnerella, Ruminococcus, Megasphaera, and Ureaplasma. Notably, the more abundant genera in RA patients were correlated with the disease activity score of 28 joints-erythrocyte sedimentation rates (DAS28-ESR) and an increase in plasma B cells. Furthermore, the altered urinary metabolites, such as proline, citric acid, and oxalic acid, were positively associated with RA patients, and they were closely correlated with urinary microbiota. These findings suggested a strong association between the altered urinary microbiota and metabolites with disease severity and dysregulated immune responses in RA patients. IMPORTANCE We revealed that the profile of the urinary tract microbiota in RA featured with increased microbial richness and shifted taxa, associated with immunological and metabolic changes of the disease, underlining the interplay between urinary microbiota and host autoimmunity.

Little is known about the prevalence and post-surgical outcomes associated with cardiac intensive care unit (CICU) therapeutics among CICU patients referred for cardiac surgery.

Rheumatoid arthritis (RA) is a systemic autoimmune disease in which T cells play a pivotal role in the pathogenesis. Knowledge in terms of the CD4 T-cell transcriptome in RA is limited. The aim of this study was to examine the whole-genome transcription profile of CD4 T cells in RA by comparing patients with RA to healthy controls.

In vitro and animal model studies suggest that transthyretin (TTR) inhibits the production of the amyloid β protein, a major contributor to Alzheimer disease (AD) pathogenesis. We evaluated the association of 16 TTR single nucleotide polymorphisms (SNPs) with AD risk in 158 African American and 469 Caucasian discordant sibships from the MIRAGE Study. There was no evidence for association of TTR with AD in either population sample. To examine the possibility that TTR SNPs affect specific components of the AD process, we tested association of these SNPs with four measures of neurodegeneration and cerebrovascular disease defined by magnetic resonance imaging (MRI) in a subset of 48 African American and 265 Caucasian sibships. Five of seven common SNPs and several haplotypes were significantly associated with hippocampal atrophy in the Caucasian sample. Two of these SNPs also showed marginal evidence for association in the African American sample. Results for the other MRI traits were unremarkable. This study highlights the potential value of neuroimaging endophenotypes as a tool for finding genes influencing AD pathogenesis.

The histone deacetylase 6 (HDAC6) plays critical roles in human tumorigenesis and metastasis. As such, HDAC6-selective inhibitors have entered clinical trials for cancer therapy. However, the upstream regulator(s), especially ubiquitin E3 ligase(s), responsible for controlling the protein stability of HDAC6 remains largely undefined. Here, we report that Cullin 3SPOP earmarks HDAC6 for poly-ubiquitination and degradation. We found that the proteasome inhibitor MG132, or the Cullin-based E3 ligases inhibitor MLN4924, but not the autophagosome-lysosome inhibitor bafilomycin A1, stabilized endogenous HDAC6 protein in multiple cancer cell lines. Furthermore, we demonstrated that Cullin 3-based ubiquitin E3 ligase(s) primarily reduced the stability of HDAC6. Importantly, we identified SPOP, an adaptor protein of Cullin 3 family E3 ligases, specifically interacted with HDAC6, and promoted its poly-ubiquitination and subsequent degradation in cells. Notably, cancer-derived SPOP mutants disrupted their binding with HDAC6 and thereby failed to promote HDAC6 degradation. More importantly, increased cellular proliferation and migration in SPOP-depleted HCT116 colon cancer cells could be partly reversed by additional depletion of HDAC6, suggesting that HDAC6 is a key downstream effector for SPOP tumor suppressor function. Together, our data identify the tumor suppressor SPOP as an upstream negative regulator for HDAC6 stability, and SPOP loss-of-function mutations might lead to elevated levels of the HDAC6 oncoprotein to facilitate tumorigenesis and metastasis in various human cancers.

Brg1/SMARCA4 serves as the ATPase and the helicase catalytic subunit for the multi-component SWI/SNF chromatin remodeling complex, which plays a pivotal role in governing chromatin structure and gene transcription. However, the upstream signaling pathways regulating Brg1 protein stability and its physiological contribution to carcinogenesis remain largely elusive. Here we report that Brg1 is a bona fide ubiquitin substrate of SCFFBW7. We reveal that CK1δ phosphorylates Brg1 at Ser31/Ser35 residues to facilitate the binding of Brg1 to FBW7, leading to ubiquitination-mediated degradation. In keeping with a tumor suppressive role of FBW7 in human gastric cancer, we find an inverse correlation between FBW7 and Brg1 expression in human gastric cancer clinical samples. Mechanistically, we find that stabilization of Brg1 in gastric cancer cells suppresses E-cadherin expression, subsequently promoting gastric cancer metastasis. Hence, this previously unknown FBW7/Brg1 signaling axis provides the molecular basis and the rationale to target Brg1 in FBW7-compromised human gastric cancers.

Although radiotherapy following mastectomy was demonstrated to reduce the recurring risk and improve the prognosis of patients with breast cancer, it is also notorious for comprehensive side effects, hence only a selected group of patients can benefit. Therefore, the screening of molecular markers capable of predicting the efficacy of radiotherapy is essential.

Recent findings have identified microbiota as crucial participants in many disease conditions, including cancers. Competing endogenous RNA (ceRNA) is regarded as a candidate mechanism involving relevant biological processes. We therefore constructed a ceRNA network using the TCGA and GEO database, to determine the potential mechanisms of microbiota-mediated colorectal carcinogenesis and progression. We found a total of 75 lncRNAs, 8 miRNAs, and 9 mRNAs in the probiotics-mediated ceRNA network and a total of 49 lncRNAs, 4 miRNAs, and 3 mRNA in the pathobiont-mediated ceRNA network, which could induce the microbiota-mediated carcinogenesis and progression. The GO and KEGG analysis indicated that the ceRNA network is mainly enriched in the metabolic process, and two unique pathways (the p53 signaling pathway and microRNA in cancer), respectively. A four-gene signature (FRMD6-AS2, DIRC3, LIFR-AS1, and MRPL23-AS1) was suggested as an independent prognostic factor. Four lncRNAs (LINC00355, KCNQ1OT1, LINC00491, and HOTAIR) were associated with poor survival. Three small molecule candidate anticancer drugs (Pentoxyverine, Rimexolone, and Doxylamine) were identified. A four-gene signature (FAM129A, BCL2, PMAIP1, and RPS6) is significantly correlated with immune infiltration level. This study provides a promising biomarker reservoir to explore the mechanism by which microbiota regulate the ceRNA network involving the immune response, and further participate in colorectal carcinogenesis and progression.

Copper plays pivotal roles in metabolic homoeostasis, but its potential role in human tumorigenesis is not well defined. Here, it is revealed that copper activates the phosphoinositide 3-kinase (PI3K)-protein kinase B (PKB, also termed AKT) oncogenic signaling pathway to facilitate tumorigenesis. Mechanistically, copper binds 3-phosphoinositide dependent protein kinase 1 (PDK1), in turn promotes PDK1 binding and subsequently activates its downstream substrate AKT to facilitate tumorigenesis. Blocking the copper transporter 1 (CTR1)-copper axis by either depleting CTR1 or through the use of copper chelators diminishes the AKT signaling and reduces tumorigenesis. In support of an oncogenic role for CTR1, the authors find that CTR1 is abnormally elevated in breast cancer, and is subjected by NEDD4 like E3 ubiquitin protein ligase (Nedd4l)-mediated negative regulation through ubiquitination and subsequent degradation. Accordingly, Nedd4l displays a tumor suppressive function by suppressing the CTR1-AKT signaling. Thus, the findings identify a novel regulatory crosstalk between the Nedd4l-CTR1-copper axis and the PDK1-AKT oncogenic signaling, and highlight the therapeutic relevance of targeting the CTR1-copper node for the treatment of hyperactive AKT-driven cancers.

We aimed to figure out the molecular network of PVT1 and EZH2 on hepatocellular carcinoma (HCC) cells growth. We also explored the interaction between PVT1, EZH2, MDM2 and P53.