NOD样受体在炎症反应中的调控作用

天然免疫(innate immunity)是机体免疫系统直接抵御病原体入侵的最初阶段,通过机体自身的特异性模式识别受体(pattern-recognition receptors,PRRs)来识别病原体特有的保守结构病原相关分子模式(pathogen-associated molecular patterns,PAMPs)。细胞内NOD样受体(NLRs)是胞浆型PRRs中的一个重要家族,病原体侵袭细胞可上调其表达,启动机体的免疫应答和炎症反应,在机体天然免疫应答中发挥独特的功能。最近有研究证明,NLRs的突变与一些人类免疫性疾病相关,并且在细菌感染和炎症反应的控制中起重要作用。该文将讨论NLRs在炎症疾病中的调控作用。     

综述:炎症小体信号通路的负调控

炎症小体(inflammasomes)活化后产生的IL-1β和IL-18等促炎因子对天然免疫和适应性免疫具有重要作用.炎症小体持续活化可引起促炎因子过度表达,导致慢性炎症和自身免疫疾病的发生.正常生理状态下,机体存在多种炎症小体负调机制,以维持免疫反应平衡.病理状态下,感染机体的病原微生物通过多种途径抑制炎症小体信号通路的活化及促炎因子的产生,以利于免疫逃逸.本文综述了机体和病原微生物对炎症小体信号通路的负调控机理.阐明炎症小体信号通路负调控机制将为感染性疾病及其他炎症小体相关炎症性疾病的治疗提供策略.     

The inflammasome: in memory of Dr. Jurg Tschopp

A decade ago, Jurg Tschopp introduced the concept of the inflammasome. This exciting discovery of a macromolecular complex that senses 'danger' and initiates the inflammatory response contributed to a renaissance in the fields of innate immunity and cell death. Jurg led the biochemical characterization of the inflammasome complex and demonstrated that spontaneous hyperactivation of this interleukin (IL)-1β processing machinery is the molecular basis of a spectrum of hereditary periodic fever syndromes, caused by mutated forms of the inflammasome scaffolding receptor, NLRP3. The identification of the underlying mechanism in these disorders has led to their now successful therapy, with the use of the IL-1 receptor antagonist in the clinic. Jurg's pioneering work has subsequently defined a number of inflammasome agonists ranging from microbial molecules expressed during infection, to triggers of sterile inflammation, most notably gout-associated uric acid crystals, asbestos, silica and nanoparticles. More recently, Jurg introduced the critical new concept of the metabolic inflammasome, which senses metabolic stress and contributes to the onset of the metabolic syndrome associated with obesity and type 2 diabetes. Jurg was an outstanding and skillful biochemist, an elegant and rigorous researcher often far ahead of his peers. He was a truly amiable person, fair, generous and inspiring, and will be most remembered for his infectious enthusiasm. We write this review article on the inflammasome in his honor and dedicate it to his memory.     

Structural Determinants of Oligomerization of the Aquaporin-4 Channel

The aquaporin (AQP) family of integral membrane protein channels mediate cellular water and solute flow. Although qualitative and quantitative differences in channel permeability, selectivity, subcellular localization, and trafficking responses have been observed for different members of the AQP family, the signature homotetrameric quaternary structure is conserved. Using a variety of biophysical techniques, we show that mutations to an intracellular loop (loop D) of human AQP4 reduce oligomerization. Non-tetrameric AQP4 mutants are unable to relocalize to the plasma membrane in response to changes in extracellular tonicity, despite equivalent constitutive surface expression levels and water permeability to wild-type AQP4. A network of AQP4 loop D hydrogen bonding interactions, identified using molecular dynamics simulations and based on a comparative mutagenic analysis of AQPs 1, 3, and 4, suggest that loop D interactions may provide a general structural framework for tetrameric assembly within the AQP family.     

Caspase-1: is IL-1 just the tip of the ICEberg?

Caspase-1, formerly known as interleukin (IL)-1-converting enzyme is best established as the protease responsible for the processing of the key pro-inflammatory cytokine IL-1β from an inactive precursor to an active, secreted molecule. Thus, caspase-1 is regarded as a key mediator of inflammatory processes, and has become synonymous with inflammation. In addition to the processing of IL-1β, caspase-1 also executes a rapid programme of cell death, termed pyroptosis, in macrophages in response to intracellular bacteria. Pyroptosis is also regarded as a host response to remove the niche of the bacteria and to hasten their demise. These processes are generally accepted as the main roles of caspase-1. However, there is also a wealth of literature supporting a direct role for caspase-1 in non-infectious cell death processes. This is true in mammals, but also in non-mammalian vertebrates where caspase-1-dependent processing of IL-1β is absent because of the lack of appropriate caspase-1 cleavage sites. This literature is most prevalent in the brain where caspase-1 may directly regulate neuronal cell death in response to diverse insults. We attempt here to summarise the evidence for caspase-1 as a cell death enzyme and propose that, in addition to the processing of IL-1β, caspase-1 has an important and a conserved role as a cell death protease.     

The death-domain fold of the ASC PYRIN domain, presenting a basis for PYRIN/PYRIN recognition

The PYRIN domain is a conserved sequence motif identified in more than 20 human proteins with putative functions in apoptotic and inflammatory signalling pathways. The three-dimensional structure of the PYRIN domain from human ASC was determined by NMR spectroscopy. The structure determination reveals close structural similarity to death domains, death effector domains, and caspase activation and recruitment domains, although the structural alignment with these other members of the death-domain superfamily differs from previously predicted amino acid sequence alignments. Two highly positively and negatively charged surfaces in the PYRIN domain of ASC result in a strong electrostatic dipole moment that is predicted to be present also in related PYRIN domains. These results suggest that electrostatic interactions play an important role for the binding between PYRIN domains. Consequently, the previously reported binding between the PYRIN domains of ASC and ASC2/POP1 or between the zebrafish PYRIN domains of zAsc and Caspy is proposed to involve interactions between helices 2 and 3 of one PYRIN domain with helices 1 and 4 of the other PYRIN domain, in analogy to previously reported homophilic interactions between caspase activation and recruitment domains.     

Modular organization of SARS coronavirus nucleocapsid protein

The SARS-CoV nucleocapsid (N) protein is a major antigen in severe acute respiratory syndrome. It binds to the viral RNA genome and forms the ribonucleoprotein core. The SARS-CoV N protein has also been suggested to be involved in other important functions in the viral life cycle. Here we show that the N protein consists of two non-interacting structural domains, the N-terminal RNA-binding domain (RBD) (residues 45–181) and the C-terminal dimerization domain (residues 248–365) (DD), surrounded by flexible linkers. The C-terminal domain exists exclusively as a dimer in solution. The flexible linkers are intrinsically disordered and represent potential interaction sites with other protein and protein-RNA partners. Bioinformatics reveal that other coronavirus N proteins could share the same modular organization. This study provides information on the domain structure partition of SARS-CoV N protein and insights into the differing roles of structured and disordered regions in coronavirus nucleocapsid proteins. CK Chang and SC Sue contributed equally to this project.     

Is there nascent structure in the intrinsically disordered region of troponin I?

In striated muscle, the binding of calcium to troponin C (TnC) results in the removal of the C‐terminal region of the inhibitory protein troponin I (TnI) from actin. While structural studies of the muscle system have been successful in determining the overall organization of most of the components involved in force generation at the atomic level, the structure and dynamics of the C‐terminal region of TnI remains controversial. This domain of TnI is highly flexible, and it has been proposed that this intrinsically disordered region (IDR) regulates contraction via a “fly‐casting” mechanism. Different structures have been presented for this region using different methodologies: a single α‐helix, a “mobile domain” containing a small β‐sheet, an unstructured region, and a two helix segment. To investigate whether this IDR has in fact any nascent structure, we have constructed a skeletal TnC‐TnI chimera that contains the N‐domain of TnC (1–90), a short linker (GGAGG), and the C‐terminal region of TnI (97–182) and have acquired ¹⁵N NMR relaxation data for this chimera. We compare the experimental relaxation parameters with those calculated from molecular dynamic simulations using four models based upon the structural studies. Our experimental results suggest that the C‐terminal region of TnI does not contain any defined secondary structure, supporting the “fly‐casting” mechanism. We interpret the presence of a “plateau” in the ¹⁵N NMR relaxation data as being an intrinsic property of IDRs. We also identified a more rigid adjacent region of TnI that has implications for muscle performance under ischemic conditions. Proteins 2011. © 2011 Wiley‐Liss, Inc.     

1H, 15N and 13C backbone and side chain chemical shifts of human ASC (apoptosis-associated speck-like protein containing a CARD domain)

The backbone and side chain resonance assignments of human ACS (∼22 KD), apoptosis-associated speck-like protein containing a caspase recruitment domain and a pyrin domain, have been determined by triple-resonance NMR techniques.