革兰阴性菌结合蛋白(Toll/GNBPs)和肽聚糖识别蛋白(PGRPs)在无脊椎动物先天免疫应答中的作用

由于无脊椎动物没有专一的特异性免疫系统,所以先天免疫系统是其抵御外来病原入侵的唯一方式,无脊椎动物的先天免疫系统包括细胞和体液防卫机制,这2种机制可被模式识别受体(PRR s)分子所触发,PRR s可与微生物表面特异的物质识别并结合,通过结合,这些PRR s通过包囊和噬菌作用直接杀死微生物,或者通过丝氨酸蛋白酶级联反应和细胞内免疫信号途径间接引发不同的防御反应以抵御病原微生物。革兰阴性菌结合蛋白(GNBPs)和肽聚糖识别蛋白(PGRPs)作为无脊椎动物先天免疫系统中的一类重要模式识别受体,在识别微生物病原并引发一系列级联反应做出免疫应答过程中起重要作用。本文主要对GNBPs和PGRPs在无脊椎动物中的研究进展及其在先天免疫应答过程中的作用机制进行综述。     

四次跨膜蛋白在病毒感染中作用的研究进展

四次跨膜蛋白（Tetraspanins,Tspans）是一个作为“细胞膜主要组织者”的跨膜糖蛋白家族。它们与其他膜蛋白横向结合形成富含Tspans的微结构域（Tetraspanin-enriched microdomains,TEMs）,在细胞表面建立了独特的平台,从而直接或间接参与病毒感染的多个阶段。Tspans在调控病毒进入、转录、复制和组装释放等阶段均发挥了重要作用。研究Tspans在病毒感染中的作用,可以为病毒感染疾病的临床药物研发提供新靶点。本文综述了Tspans在病毒感染中作用的研究进展。     

细胞自噬在HIV病毒发病机理中的作用

细胞自噬是真核细胞在长期进化过程中形成的一种自我保护机制．通过溶酶体途径将胞质蛋白和细胞器降解为小分子．从而为饥饿状态下的细胞提供能量。此外,细胞自噬还能清除入侵的病原性微生物,在天然性和适应性免疫中发挥重要作用。然而近年来研究发现,细胞自噬不仅不能清除HIV病毒,反而有助于HIV病毒的复-a4。此外,HIV病毒蛋白似乎能够阻断细胞自噬作用．促进CD4＋T淋巴细胞死亡和艾滋病的发生。简要介绍了细胞自噬的机制。以及细胞自噬在HIV病毒感染中的病理、生理作用。研究细胞自噬与HIV病毒之间的相互作用．有望发现治疗艾滋病的新靶点。     

无脊椎动物病毒研究的某些进展

无脊椎动物占地球上整个动物种的80％,据Martignoni等的统计,从无脊椎动物中分离的病毒约1288种,其中绝大多数为昆虫病毒,有1255种,螨类的病毒16种,除昆虫和螨类外的其他无脊椎动物病毒约17种。 昆虫病毒中的杆状病毒,其形态结构和形态发生十分特殊,在整个病毒学中占有重要地     

细胞自噬与病毒复制

细胞自噬是真核生物中一种高度保守的细胞内容物降解过程,在维持细胞的内环境稳定中起着重要作用。同时,自噬参与固有免疫系统对病原微生物的识别,以帮助吞噬细胞进行有效的吞噬作用并清除细胞内外的病原体。而病毒,尤其是RNA病毒,具有快速进化以应对宿主细胞中的变化的能力,能通过利用或抑制宿主细胞的自噬作用来为自身的复制服务。因此,针对自噬途径的药物筛选和治疗策略越来越成为抗病毒研究的热点。     

无脊椎动物清道夫受体的免疫调控

在长期进化的过程中,无脊椎动物逐渐形成了受体识别-信号传导-免疫应答为特征的天然免疫体系,以清除凋亡细胞或外界的病原微生物。清道夫受体（SRs）是一类位于细胞表面的跨膜受体,也是一类参与无脊椎动物天然免疫反应的重要模式识别受体。清道夫受体参与免疫反应的异己靶标识别,通过下游信号级联调控抗菌肽合成和吞噬作用。本文综述了无脊椎动物清道夫受体的种类、结构及其参与天然免疫的调控机制,探讨了无脊椎动物清道夫受体研究中尚待解决的问题。     

杆状病毒糖蛋白的结构与功能

杆状病毒是以无脊椎动物为专性寄主的多家族病毒,作为有效的生物杀虫剂,有着广泛的应用前景。它所含的糖蛋白在病毒繁殖、感染宿主的生命周期中,特别是在细胞识别、分泌以及在蛋白质的加工、折叠和稳定方面,都起着不容忽视的重要作用。不同的糖蛋白,不同的连接方式具有不同的功能。研究表明,N聚糖的初级作用是诱导其发挥功能所必需的构象,杆状病毒GP64蛋白是一种受体细胞连接蛋白,也是病毒粒子端粒的成分。GP37糖蛋白可能在昆虫病毒复制周期中起重要作用。在研究细胞质和细胞核内的蛋白质的糖基化水平发现,当T淋巴细胞激活时,核内糖基化水平迅速增加,而细胞质内的蛋白质糖基化水平则降低。因此在生物合成期间,糖蛋白缺乏某些聚糖或阻断糖基化的某一步都会使分子在细胞内的运输受损及其功能异常。     

细胞自噬与病毒复制

细胞自噬是真核生物中一种高度保守的细胞内容物降解过程,在维持细胞的内环境稳定中起着重要作用。同时,自噬参与固有免疫系统对病原微生物的识别,以帮助吞噬细胞进行有效的吞噬作用并清除细胞内外的病原体。而病毒,尤其是RNA病毒,具有快速进化以应对宿主细胞中的变化的能力,能通过利用或抑制宿主细胞的自噬作用来为自身的复制服务。因此,针对自噬途径的药物筛选和治疗策略越来越成为抗病毒研究的热点。     

Toll样受体4与病毒感染的研究进展

Toll样受体4（TLR4）是固有免疫系统中能够识别病原相关分子模式的受体家族成员,可识别革兰氏阴性菌的脂多糖（LPS）而在细菌感染性疾病的发生中起重要作用。近年来越来越多的研究发现,TLR4还广泛参与病毒感染性疾病的发生和病毒的免疫逃逸,由于其信号转导通路的独特性和细胞定位的可变性,再次引起人们极大的研究兴趣。该文将介绍TLR4的生物学特性、信号转导通路及TLR4与病毒感染的最新研究进展。     

昆虫类免疫球蛋白结构和功能研究进展

类免疫球蛋白是在无脊椎动物体内发现的唯一的免疫球蛋白家族成员,它对鳞翅目昆虫自身的免疫起着重要的作用。已有研究表明：类免疫球蛋白只存在于鳞翅目昆虫体内,有可溶性和不溶性两种存在方式,在昆虫体内分别具有不同的功能。可溶性类免疫球蛋白通过一些酶和蛋白的作用对入侵昆虫的细菌和病毒进行免疫防御,而不溶性类免疫球蛋白（即以膜结合蛋白的形式出现）对细胞和细胞黏着以及病毒和细菌入侵细胞有着延缓作用。     

The ekeko mutant demonstrates a role for tetraspanin-like protein in plant development

A new mutant with disturbed cell differentiation and severely altered plant morphology was obtained by visual screening of a T-DNA mutagenized population of Arabidopsis thaliana. The T-DNA in this mutant was inserted in an unknown gene (ORF At5g46700) located on chromosome V. This gene and additional 12 genes in the Arabidopsis genome show structural homologies to a class of abundantly expressed mammalian proteins with four transmembrane domains (TM4) called tetraspanins. In animals tetraspanins are involved in different cell functions like cell development, adhesion, motility, and differentiation, probably by organizing other proteins into a network of multimolecular membrane microdomains, called the tetraspanin web. So far no function for tetraspanins in plants has been described. Here, we show that a mutation in the TM4-like gene EKEKO results in severe developmental defects that could be the result of incorrect regulation of cell differentiation.     

Tetraspanins in the humoral immune response

The tetraspanins represent a large superfamily of four-transmembrane proteins that are expressed on all nucleated cells. Tetraspanins play a prominent role in the organization of the plasma membrane by co-ordinating the spatial localization of transmembrane proteins and signalling molecules into 'tetraspanin microdomains'. In immune cells, tetraspanins interact with key leucocyte receptors [including MHC molecules, integrins, CD4/CD8 and the BCR (B-cell receptor) complex] and as such can modulate leucocyte receptor activation and downstream signalling pathways. There is now ample evidence that tetraspanins on B-lymphocytes are important in controlling antibody production. The tetraspanin CD81 interacts with the BCR complex and is critical for CD19 expression and IgG production, whereas the tetraspanin CD37 inhibits IgA production and is important for IgG production. By contrast, the tetraspanins CD9, Tssc6 and CD151 appear dispensable for humoral immune responses. Thus individual tetraspanin family members have specific functions in B-cell biology, which is evidenced by recent studies in tetraspanin-deficient mice and humans. The present review focuses on tetraspanins expressed by B-lymphocytes and discusses novel insights into the function of tetraspanins in the humoral immune response.     

Blocking the large extracellular loop (LEL) domain of FcTetraspanin-3 could inhibit the infection of white spot syndrome virus (WSSV) in Chinese shrimp, Fenneropenaeus chinensis

Tetraspanins belong to the transmembrane 4 superfamily (TM(4)SF), which span the cell membrane 4 times and act as bridges or connectors. Increasing evidences have shown that tetraspanins play important role in virus infection. The large extracellular loop (LEL) of a tetraspanin is considered as a possible target of some virus. Tetraspanins are widely found in invertebrates, but the functional roles of most invertebrate tetraspanins have remained unknown. Recently, a tetraspanin, called FcTetraspanin-3, was cloned from the cDNA library of Chinese shrimp, Fenneropenaeus chinensis. The FcTetraspanin-3 constitutive expression in all examined tissues and the expression of the gene were highly induced in hepatopancreas, lymphoid organ and intestine by white spot syndrome virus (WSSV) challenge. In this study, we expressed and purified the recombinant peptide containing the LEL domain of FcTetraspanin-3, and produced the anti-LEL polyclone antibody. The expression of FcTetraspanin-3 was observed by real-time PCR and Western blot. Also, the localization of FcTetraspanin-3-positive cells in intestine and hepatopancreas were revealed by immunofluorescence. The results of anti-LEL antibody blocking experiments shown that the antibody can significantly reduce the mortality of shrimp challenged by WSSV. Additionally, dsRNA interference was utilized to examine the functional role of FcTetraspanin-3 in response to WSSV infection, and a sensible decrease of the viral copy number in the tetraspanin knockdown shrimp. These results suggested the blocking of LEL domain of FcTetraspanin-3 could inhibit the infection of WSSV. FcTetraspanin-3 might play an important role in response to WSSV infection, and the LEL domain of FcTetraspanin-3 might mediate the entry of WSSV.     

Tetraspanins: Interactions and interplay with integrins

Tetraspanins are small transmembrane proteins present on the cell surface of almost every eukaryotic cell. Through binding with other transmembrane and intracellular proteins, they regulate diverse cellular processes ranging from cell adhesion and motility to synapse formation and tumor progression. Here, we provide a brief overview of molecular, cellular and clinical studies to illustrate how the multiple functions of this fascinating family of molecules stem from their interplay with multiple molecular partners. In particular, we emphasize the special relationship between tetraspanins and the cell adhesion molecules integrins in regulating cell physiology in health and disease.     

The TspanC8 Subgroup of Tetraspanins Interacts with A Disintegrin and Metalloprotease 10 (ADAM10) and Regulates Its Maturation and Cell Surface Expression

A disintegrin and metalloprotease 10 (ADAM10) is a ubiquitous transmembrane metalloprotease that cleaves the extracellular regions from over 40 different transmembrane target proteins, including Notch and amyloid precursor protein. ADAM10 is essential for embryonic development and is also important in inflammation, cancer, and Alzheimer disease. However, ADAM10 regulation remains poorly understood. ADAM10 is compartmentalized into membrane microdomains formed by tetraspanins, which are a superfamily of 33 transmembrane proteins in humans that regulate clustering and trafficking of certain other transmembrane “partner” proteins. This is achieved by specific tetraspanin-partner interactions, but it is not clear which tetraspanins specifically interact with ADAM10. The aims of this study were to identify which tetraspanins interact with ADAM10 and how they regulate this metalloprotease. Co-immunoprecipitation identified specific ADAM10 interactions with Tspan5, Tspan10, Tspan14, Tspan15, Tspan17, and Tspan33/Penumbra. These are members of the largely unstudied TspanC8 subgroup of tetraspanins, all six of which promoted ADAM10 maturation. Different cell types express distinct repertoires of TspanC8 tetraspanins. Human umbilical vein endothelial cells express relatively high levels of Tspan14, the knockdown of which reduced ADAM10 surface expression and activity. Mouse erythrocytes express predominantly Tspan33, and ADAM10 expression was substantially reduced in the absence of this tetraspanin. In contrast, ADAM10 expression was normal on Tspan33-deficient mouse platelets in which Tspan14 is the major TspanC8 tetraspanin. These results define TspanC8 tetraspanins as essential regulators of ADAM10 maturation and trafficking to the cell surface. This finding has therapeutic implications because focusing on specific TspanC8-ADAM10 complexes may allow cell type- and/or substrate-specific ADAM10 targeting.     

Exosome target cell selection and the importance of exosomal tetraspanins: a hypothesis

Exosomes are derived from limiting membranes of MVBs (multivesicular bodies). They carry and transfer selected membrane and cytoplasmic proteins, mRNA and microRNA into target cells. It is due to this shipping of information that exosomes are considered to be the most promising therapeutic tool for multiple diseases. However, whereas knowledge on the composition of exosomes is rapidly increasing, the mode of selective recruitment into exosomes as well as target cell selection is poorly understood. We suggest that at least part of this task is taken over by tetraspanins. Tetraspanins, which are involved in morphogenesis, fission and fusion processes, are enriched in exosomes, and our previous work revealed that the recruitment of distinct tetraspanins into exosomes follows very selective routes, including a rearrangement of the tetraspanin web. Furthermore, only exosomes expressing a defined set of tetraspanins and associated molecules target endothelial cells, thereby contributing to angiogenesis and vasculogenesis. On the basis of these findings we hypothesize (i) that the protein assembly of exosomes and possibly the recruitment of microRNA will be regulated to a large extent by tetraspanins and (ii) that tetraspanins account for target cell selection and the tight interaction/uptake of exosomes by the target cell. Exosomes herald an unanticipated powerful path of cell-cell communication. An answer to how exosomes collect and transfer information will allow the use of Nature's concept to cope with malfunctions.     

Building of the tetraspanin web: distinct structural domains of CD81 function in different cellular compartments

The tetraspanin web is composed of a network of tetraspanins and their partner proteins that facilitate cellular interactions and fusion events by an unknown mechanism. Our aim was to unravel the web partnership between the tetraspanin CD81 and CD19, a cell surface signaling molecule in B lymphocytes. We found that CD81 plays multiple roles in the processing, intracellular trafficking, and membrane functions of CD19. Surprisingly, these different roles are embodied in distinct CD81 domains, which function in the different cellular compartments: the N-terminal tail of CD81 has an effect on the glycosylation of CD19; the first transmembrane domain of CD81 is sufficient to support the exit of CD19 from the endoplasmic reticulum, although the large extracellular loop (LEL) of CD81 associates physically with CD19 early during biosynthesis; and finally, the TM2 and TM3 domains of CD81 play a role in the transmission of signals initiated upon engagement of the LEL. The participation of distinct CD81 domains in varied functions may explain the pleiotropic effects of CD81 within the tetraspanin web.     

The tetraspanin web modulates immune-signalling complexes

The tetraspanin web represents a new concept of molecular interactions in the immune system. Whereas most surface immune-modulating molecules involve receptor-ligand interactions, tetraspanins associate with partner proteins and facilitate their lateral positioning in the membrane. Moreover, the same tetraspanin molecule can associate with different proteins depending on the cell type. Most importantly, members of this family tend to associate with each other, together with their partners, in membrane microdomains that provide a scaffold for the transmission of external stimuli to intracellular-signalling components.     

Characterization of integrin-tetraspanin adhesion complexes: role of tetraspanins in integrin signaling.

Tetraspanins (or proteins from the transmembrane 4 superfamily, TM4SF) form membrane complexes with integrin receptors and are implicated in integrin-mediated cell migration. Here we characterized cellular localization, structural composition, and signaling properties of alpha3beta1-TM4SF adhesion complexes. Double-immunofluorescence staining showed that various TM4SF proteins, including CD9, CD63, CD81, CD82, and CD151 are colocalized within dot-like structures that are particularly abundant at the cell periphery. Differential extraction in conjunction with chemical cross-linking indicated that the cell surface fraction of alpha3beta1-TM4SF protein complexes may not be directly linked to the cytoskeleton. However, in cells treated with cytochalasin B alpha3beta1-TM4SF protein complexes are relocated into intracellular vesicles suggesting that actin cytoskeleton plays an important role in the distribution of tetraspanins into adhesion structures. Talin and MARCKS are partially codistributed with TM4SF proteins, whereas vinculin is not detected within the tetraspanin-containing adhesion structures. Attachment of serum-starved cells to the immobilized anti-TM4SF mAbs induced dephosphorylation of focal adhesion kinase (FAK). On the other hand, clustering of tetraspanins in cells attached to collagen enhanced tyrosine phosphorylation of FAK. Furthermore, ectopic expression of CD9 in fibrosarcoma cells affected adhesion-induced tyrosine phosphorylation of FAK, that correlated with the reorganization of the cortical actin cytoskeleton. These results show that tetraspanins can modulate integrin signaling, and point to a mechanism by which TM4SF proteins regulate cell motility.