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White spot syndrome virus (WSSV) is an enveloped double-stranded DNA virus that has had a serious influence on worldwide shrimp farming in the last 30 years. We have demonstrated that WSSV hijacks host autophagy and lipid metabolism for reproduction in kuruma shrimp ( Marsupenaeus japonicus ). These findings revealed the mechanism by which WSSV exploits host machinery for its infection and provided serial targets for WSSV prevention and control in shrimp farming. Mindin is a secreted extracellular matrix protein that is involved in regulating cellular events through interacting with integrin. Studies have demonstrated its role in host immunity, including phagocytosis, cell migration, and cytokine production. However, the function of Mindin in the host-virus interaction is largely unknown. In the present study, we report that Mindin facilitates virus infection by activating lipid utilization in an arthropod, kuruma shrimp ( Marsupenaeus japonicus ). Shrimp Mindin facilitates white spot syndrome virus infection by facilitating viral entry and replication. By activating autophagy, Mindin induces lipid droplet consumption, the hydrolysis of triglycerides into free fatty acids, and ATP production, ultimately providing energy for virus infection. Moreover, integrin is essential for Mindin-mediated autophagy and lipid utilization. Therefore, by revealing the mechanism by which Mindin facilitates virus infection through regulating lipid metabolism, the present study reveals the significance of Mindin in the host-virus interaction. IMPORTANCE White spot syndrome virus (WSSV) is an enveloped double-stranded DNA virus that has had a serious influence on worldwide shrimp farming in the last 30 years. We have demonstrated that WSSV hijacks host autophagy and lipid metabolism for reproduction in kuruma shrimp ( Marsupenaeus japonicus ). These findings revealed the mechanism by which WSSV exploits host machinery for its infection and provided serial targets for WSSV prevention and control in shrimp farming.

Background Acute renal injury (AKI) secondary to ischemia reperfusion (IR) injury continues to be a significant perioperative problem and there is no effective treatment. Mindin belongs to the mindin/F-spondin family and involves in inflammation, proliferation, and cell apoptosis. Previous studies have explored the biological functions of mindin in liver and brain ischemic injury, but its role in AKI is unknown. Method To investigate whether mindin has a pathogenic role, mindin knockout (KO) and wild-type (WT) mice were used to establish renal IR model. After 30 min of ischemia and 24 h of reperfusion, renal histology, serum creatinine, and inflammatory response were examined to assess kidney injury. In vitro, proinflammatory factors and inflammatory signaling pathways were measured in mindin overexpression or knockdown and vector cells after hypoxia/reoxygenation (HR). Results Following IR, the kidney mindin level was increased in WT mice and deletion of mindin provided significant protection for mice against IR-induced renal injury as manifested by attenuated the elevation of serum creatinine and blood urea nitrogen along with less severity for histological alterations. Mindin deficiency significantly suppressed inflammatory cell infiltration, TNF-α and MCP-1 production following renal IR injury. Mechanistic studies revealed that mindin deficiency inhibits TLR4/JNK/NF-κB signaling activation. In vitro, the expression levels of TNF-α and MCP-1 were increased in mindin overexpression cells compared with vector cells following HR. Moreover, TLR4/JNK/NF-κB signaling activation was elevated in the mindin overexpression cells in response to HR stimulation while mindin knockdown inhibited the activation of TLR4/JNK/ NF-κB signaling after HR in vitro. Further study showed that mindin protein interacted directly with TLR4 protein. And more, mindin protein was confirmed to be expressed massively in renal tubule tissues of human hydronephrosis patients. Conclusion These data demonstrate that mindin is a critical modulator of renal IR injury through regulating inflammatory responses. TLR4/JNK/NF-κB signaling most likely mediates the biological function of mindin in this model of renal ischemia.

Mindin, a secreted, highly conserved extracellular matrix (ECM) protein, exerts a broad spectrum of effects on the innate immune system. However, its function in colorectal cancer (CRC) progression is not well established, and its upstream regulation mechanisms remain unclear. Contrary to previous reports, this study used two different enzyme-linked immunosorbent assay (ELISA) kits to show that the serum level of mindin was significantly decreased in CRC patients and that this decreased level is more significantly associated with the early stages of the disease. To explore the regulation of mindin, we used a bioinformatics approach to predict potential transcription factors and determined that early growth response factor (Egr)-1 directly regulates mindin expression at the transcriptional level using dual luciferase, chromatin immunoprecipitation (ChIP) DNA and electrophoretic mobility shift assay (EMSA) methods. Egr-1 regulates mindin mRNA and protein expression in CRC cells, and the protein expression of both Egr-1 and mindin was significantly decreased in tumor lesions of patients compared with adjacent control tissues. Mindin is essential for Egr-1-mediated inhibition of endothelial cell tube formation, and mindin inhibits endotheliocyte proliferation, migration and angiogenic sprouts in vitro . Overexpression of mindin suppressed xenograft tumor growth by blocking angiogenesis instead of directly suppressing CRC cell proliferation. Mechanically, mindin inhibits the hypoxia-induced HIF-1a and VEGFA protein expression in CRC cells and the phosphorylation of VEGFR-2 in endothelial cells. The results suggest that the serum level of mindin can be used as a novel biomarker for early detection of CRC and that the Egr-1/mindin axis is a potential therapeutic target for the inhibition of angiogenesis in CRC development.

Renal fibrosis acts as a clinical predictor in patients with chronic kidney disease and is characterized by excessive extracellular matrix (ECM) accumulation. Our previous study suggested that mindin can function as a mediator for liver steatosis pathogenesis. However, the role of mindin in renal fibrosis remains obscure. Here, tumour necrosis factor (TGF)‐β‐treated HK‐2 cells and global mindin knockout mouse were induced with renal ischaemia reperfusion injury (IRI) to test the relationship between mindin and renal fibrosis. In vitro, mindin overexpression promoted p65—the hub subunit of the NF‐κB signalling pathway—translocation from the cytoplasm into the nucleus, resulting in NF‐κB pathway activation in TGF‐β‐treated HK‐2 cells. Meanwhile, mindin activated the TGF‐β/Smad pathway, thereby causing fibrotic‐related protein expression in vitro. Mindin−/− mice exhibited less kidney lesions than controls, with small renal tubular expansion, inflammatory cell infiltration, as well as collagen accumulation, following renal IRI. Mechanistically, mindin−/− mice suppressed p65 translocation and deactivated NF‐κB pathway. Simultaneously, mindin disruption inhibited the TGF‐β/Smad pathway, alleviating the expression of ECM‐related proteins. Hence, mindin may be a novel target of renal IRI in the treatment of renal fibrogenesis.

Mindin (spondin‐2) is an extracellular matrix protein of unknown structure that is required for efficient T‐cell priming by dendritic cells. Additionally, mindin functions as a pattern recognition molecule for initiating innate immune responses. These dual functions are mediated by interactions with integrins and microbial pathogens, respectively. Mindin comprises an N‐terminal F‐spondin (FS) domain and C‐terminal thrombospondin type 1 repeat (TSR). We determined the structure of the FS domain at 1.8‐Å resolution. The structure revealed an eight‐stranded antiparallel β‐sandwich motif resembling that of membrane‐targeting C2 domains, including a bound calcium ion. We demonstrated that the FS domain mediates integrin binding and identified the binding site by mutagenesis. The mindin FS domain therefore represents a new integrin ligand. We further showed that mindin recognizes lipopolysaccharide (LPS) through its TSR domain, and obtained evidence that C‐mannosylation of the TSR influences LPS binding. Through these dual interactions, the FS and TSR domains of mindin promote activation of both adaptive and innate immune responses.

Mindin has a broad spectrum of roles in the innate immune system, including in macrophage migration, antigen phagocytosis and cytokine production. Mindin functions as a pattern‐recognition molecule for microbial pathogens. However, the underlying mechanisms of mindin‐mediated phagocytosis and its exact membrane receptors are not well established. Herein, we generated mindin‐deficient mice using the CRISPR‐Cas9 system and show that peritoneal macrophages from mindin‐deficient mice were severely defective in their ability to phagocytize E  coli. Phagocytosis was enhanced when E  coli or fluorescent particles were pre‐incubated with mindin, indicating that mindin binds directly to bacteria or non‐pathogen particles and promotes phagocytosis. We defined that 131I‐labelled mindin binds with integrin Mac‐1 (CD11b/CD18), the F‐spondin (FS)‐fragment of mindin binds with the αM‐I domain of Mac‐1 and that mindin serves as a novel ligand of Mac‐1. Blockade of the αM‐I domain of Mac‐1 using either a neutralizing antibody or si‐Mac‐1 efficiently blocked mindin‐induced phagocytosis. Furthermore, mindin activated the Syk and MAPK signalling pathways and promoted NF‐κB entry into the nucleus. Our data indicate that mindin binds with the integrin Mac‐1 to promote macrophage phagocytosis through Syk activation and NF‐κB p65 translocation, suggesting that the mindin/Mac‐1 axis plays a critical role during innate immune responses.

Mindin is important in broad spectrum of immune responses. On the other hand, we previously reported that mindin attenuated human colon cancer development by blocking angiogenesis through Egr‐1–mediated regulation. However, the mice original mindin directly suppressed the syngenic colorectal cancer (CRC) growth in our recent study and we aimed to further define the role of mindin during CRC development in mice. We established the mouse syngeneic CRC CMT93 and CT26 WT cell lines with stable mindin knock‐down or overexpression. These cells were also subcutaneously injected into C57BL/6 and BALB/c mice as well as established a colitis‐associated colorectal cancer (CAC) mouse model treated with lentiviral‐based overexpression and knocked‐down of mindin. Furthermore, we generated mindin knockout mice using a CRISPR‐Cas9 system with CAC model. Our data showed that overexpression of mindin suppressed cell proliferation in both of CMT93 and CT26 WT colon cancer cell lines, while the silencing of mindin promoted in vitro cell proliferation via the ERK and c‐Fos pathways and cell cycle control. Moreover, the overexpression of mindin significantly suppressed in vivo tumour growth in both the subcutaneous transplantation and the AOM/DSS‐induced CAC models. Consistently, the silencing of mindin reversed these in vivo observations. Expectedly, the tumour growth was promoted in the CAC model on mindin‐deficient mice. Thus, mindin plays a direct tumour suppressive function during colon cancer progression and suggesting that mindin might be exploited as a therapeutic target for CRC.

Advanced prostate cancer preferential metastasis to bone is associated with osteomimicry. MINDIN is a secreted matrix protein upregulated in prostate tumors that overexpresses bone-related genes during prostate cancer progression. Na+/H+ exchanger regulatory factor (NHERF-1) is a scaffold protein that has been involved both in tumor regulation and osteogenesis. We hypothesize that NHERF-1 modulation is a mechanism used by MINDIN to promote prostate cancer progression. We analyzed the expression of NHERF-1 and MINDIN in human prostate samples and in a premetastatic prostate cancer mouse model, based on the implantation of prostate adenocarcinoma TRAMP-C1 (transgenic adenocarcinoma of the mouse prostate) cells in immunocompetent C57BL/6 mice. The relationship between NHERF-1 and MINDIN and their effects on cell proliferation, migration, survival and osteomimicry were evaluated. Upregulation of MINDIN and downregulation of NHERF-1 expression were observed both in human prostate cancer samples and in the TRAMP-C1 model. MINDIN silencing restored NHERF-1 expression to control levels in the mouse model. Stimulation with MINDIN reduced NHERF-1 expression and triggered its mobilization from the plasma membrane to the cytoplasm in TRAMP-C1 cells. MINDIN-dependent downregulation of NHERF-1 promoted tumor cell migration and proliferation without affecting osteomimicry and adhesion. We propose that MINDIN downregulates NHERF-1 expression leading to promotion of processes involved in prostate cancer progression.

目的 分析聚乙二醇干扰素α-2b (PEG-IFNα-2b) 治疗慢性乙型肝炎 (CHB) 过程中Mindin蛋白的变化以及作用。 方法 选取2018年1月—2019年12月于西安交通大学第二附属医院行PEG-IFNα-2b治疗的CHB患者29例，按照临床结局分为治愈组 (n=17) 与未治愈组 (n=12) 。分别采集治愈组和未治愈组基线、12周和24周的外周血样本，测量血常规、肝功能、乙型肝炎标志物定量和Mindin蛋白含量。分析比较各时间点HBsAg、ALT、AST及Minidn蛋白水平的组间差异。符合正态分布的计量资料两组间比较采用成组t检验；非正态分布的计量资料两组间比较采用Mann-Whitney U检验。采用Spearman相关性分析法对Mindin蛋白与HBsAg、ALT、AST的相关性进行分析。多元线性回归分析探讨HBsAg、ALT水平对Mindin蛋白的影响。 结果 基线资料分析发现，未治愈组和治愈组HBsAg、抗-HBe、Alb和白/球比值 (A/G) 水平两组间比较差异均有统计学意义 (P值均<0.05) 。治愈组Mindin蛋白水平呈现持续上升的趋势，24周时Mindin蛋白水平显著高于基线 (P<0.05) 。24周时治愈组Mindin蛋白水平显著高于未治愈组 (P=0.019) 。治愈组HBsAg水平均显著低于未治愈组，且组内各时间点与基线比较差异均具有统计学意义 (P值均<0.05) 。此外，治愈组ALT和AST的变化均呈现先升高后降低的趋势，12周的表达水平均显著高于基线 (P值均<0.05) 。未治愈组24周ALT和AST水平均显著高治愈组 (P值均<0.05) 。未治愈组12周时Mindin蛋白水平与ALT呈现出较强的直线相关性 (r=0.760 8，P<0.05) ，进一步的多元线性回归分析同样证明两者间存在线性关系 (偏回归系数为1.571，P=0.019) 。 结论 PEG-IFNα-2b抗病毒治疗24周时的Mindin蛋白水平在治愈组和未治愈组间存在明显差异。提示通过检测Mindin蛋白的动态变化可以更好地预测慢性乙型肝炎的治疗结局，为临床提供参考。

Cardiac hypertrophy is a response of the myocardium to increased workload and is characterised by an increase of myocardial mass and an accumulation of extracellular matrix (ECM). As an ECM protein, an integrin ligand, and an angiogenesis inhibitor, all of which are key players in cardiac hypertrophy, mindin is an attractive target for therapeutic intervention to treat or prevent cardiac hypertrophy and heart failure. In this study, we investigated the role of mindin in cardiac hypertrophy using littermate Mindin knockout ( Mindin −/− ) and wild-type (WT) mice. Cardiac hypertrophy was induced by aortic banding (AB) or angiotensin II (Ang II) infusion in Mindin −/− and WT mice. The extent of cardiac hypertrophy was quantitated by echocardiography and by pathological and molecular analyses of heart samples. Mindin −/− mice were more susceptible to cardiac hypertrophy and fibrosis in response to AB or Ang II stimulation than wild type. Cardiac function was also markedly exacerbated during both systole and diastole in Mindin −/− mice in response to hypertrophic stimuli. Western blot assays further showed that the activation of AKT/glycogen synthase kinase 3β (GSK3β) signalling in response to hypertrophic stimuli was significantly increased in Mindin −/− mice. Moreover, blocking AKT/GSK3β signalling with a pharmacological AKT inhibitor reversed cardiac abnormalities in Mindin −/− mice. Our data show that mindin, as an intrinsic cardioprotective factor, prevents maladaptive remodelling and the transition to heart failure by blocking AKT/GSK3β signalling.