SHARPIN is a component of the NF-κB-activating linear ubiquitin chain assembly complex

Cpdm (chronic proliferative dermatitis) mice develop chronic dermatitis and an immunodeficiency with increased serum IgM, symptoms that resemble those of patients with X-linked hyper-IgM syndrome and hypohydrotic ectodermal dysplasia (XHM-ED), which is caused by mutations in NEMO (NF-κB essential modulator; also known as IKBKG). Spontaneous null mutations in the Sharpin (SHANK-associated RH domain interacting protein in postsynaptic density) gene are responsible for the cpdm phenotype in mice. SHARPIN shows significant similarity to HOIL-1L (also known as RBCK1), a component of linear ubiquitin chain assembly complex (LUBAC), which induces NF-κB activation through conjugation of linear polyubiquitin chains to NEMO. Here, we identify SHARPIN as an additional component of LUBAC. SHARPIN-containing complexes can linearly ubiquitinate NEMO and activated NF-κB. Thus, we re-define LUBAC as a complex containing SHARPIN, HOIL-1L, and HOIP (also known as RNF31). Deletion of SHARPIN drastically reduced the amount of LUBAC, which resulted in attenuated TNF-α- and CD40-mediated activation of NF-κB in mouse embryonic fibroblasts (MEFs) or B cells from cpdm mice. Considering the pleomorphic phenotype of cpdm mice, these results confirm the predicted role of LUBAC-mediated linear polyubiquitination in NF-κB activation induced by various stimuli, and strongly suggest the involvement of LUBAC-induced NF-κB activation in various disorders.     

E3 ubiquitin ligase that recognizes sugar chains

N-glycosylation of proteins in the endoplasmic reticulum (ER) has a central role in protein quality control. Here we report that N-glycan serves as a signal for degradation by the Skp1-Cullin1-Fbx2-Roc1 (SCF(Fbx2)) ubiquitin ligase complex. The F-box protein Fbx2 (ref. 4) binds specifically to proteins attached to N-linked high-mannose oligosaccharides and subsequently contributes to ubiquitination of N-glycosylated proteins. Pre-integrin beta 1 is a target of Fbx2; these two proteins interact in the cytosol after inhibition of the proteasome. In addition, expression of the mutant Fbx2 Delta F, which lacks the F-box domain that is essential for forming the SCF complex, appreciably blocks degradation of typical substrates of the ER-associated degradation pathway. Our results indicate that SCF(Fbx2) ubiquitinates N-glycosylated proteins that are translocated from the ER to the cytosol by the quality control mechanism.     

昆虫翅膀的运动参数测量研究

研究可用于精确测量昆虫运动参数的条纹投影法.应用具有高衍射效率的声光调制器(AOD)生成投影条纹,通过调整各衍射光束的角度获得不同角间距的条纹,可用来测量反射比较低的昆虫翅膀.结合AOD和光栅,从两个相互垂直的方向投射条纹,可以在>90°的测量范围内测量蜜蜂的拍打翅膀.结果表明,在蜜蜂的一个拍打周期内,用该方法可以有效地测量其拍打角、滞后角,扭转角和扭转变形,相对测量误差<2%.     

日本传统“诗吟”中单个反射声优选时延与自相关函数的关系

研究在日本传统“诗吟”表演中，在干信号中加上适当时延的单个反射声是否更为有利．专业“诗吟”表演者嗓音中对典型的“节”的吟唱是该种表演艺术的一种独特的吟咏方式．对此及对“节”外内容的吟唱都在消音室中加以录音．文中通过成对比较法试验得出了主观优选的标度值．结果表明，在聆听对“节”的吟唱时，听者更喜欢在干信号中加上延时为10～30ms的单个反射声，而在聆听对“节”外内容的吟唱时，加上单个反射声与否对听者而言并无显著的差别．文中对此项发现从吟唱“节”的声源信号的自相关函数的包络特征上加以讨论．     

ACE2 links amino acid malnutrition to microbial ecology and intestinal inflammation

Malnutrition affects up to one billion people in the world and is a major cause of mortality. In many cases, malnutrition is associated with diarrhoea and intestinal inflammation, further contributing to morbidity and death. The mechanisms by which unbalanced dietary nutrients affect intestinal homeostasis are largely unknown. Here we report that deficiency in murine angiotensin I converting enzyme (peptidyl-dipeptidase A) 2 (Ace2), which encodes a key regulatory enzyme of the renin-angiotensin system (RAS), results in highly increased susceptibility to intestinal inflammation induced by epithelial damage. The RAS is known to be involved in acute lung failure, cardiovascular functions and SARS infections. Mechanistically, ACE2 has a RAS-independent function, regulating intestinal amino acid homeostasis, expression of antimicrobial peptides, and the ecology of the gut microbiome. Transplantation of the altered microbiota from Ace2 mutant mice into germ-free wild-type hosts was able to transmit the increased propensity to develop severe colitis. ACE2-dependent changes in epithelial immunity and the gut microbiota can be directly regulated by the dietary amino acid tryptophan. Our results identify ACE2 as a key regulator of dietary amino acid homeostasis, innate immunity, gut microbial ecology, and transmissible susceptibility to colitis. These results provide a molecular explanation for how amino acid malnutrition can cause intestinal inflammation and diarrhoea.     

Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1beta production

Systems for protein degradation are essential for tight control of the inflammatory immune response. Autophagy, a bulk degradation system that delivers cytoplasmic constituents into autolysosomes, controls degradation of long-lived proteins, insoluble protein aggregates and invading microbes, and is suggested to be involved in the regulation of inflammation. However, the mechanism underlying the regulation of inflammatory response by autophagy is poorly understood. Here we show that Atg16L1 (autophagy-related 16-like 1), which is implicated in Crohn's disease, regulates endotoxin-induced inflammasome activation in mice. Atg16L1-deficiency disrupts the recruitment of the Atg12-Atg5 conjugate to the isolation membrane, resulting in a loss of microtubule-associated protein 1 light chain 3 (LC3) conjugation to phosphatidylethanolamine. Consequently, both autophagosome formation and degradation of long-lived proteins are severely impaired in Atg16L1-deficient cells. Following stimulation with lipopolysaccharide, a ligand for Toll-like receptor 4 (refs 8, 9), Atg16L1-deficient macrophages produce high amounts of the inflammatory cytokines IL-1beta and IL-18. In lipopolysaccharide-stimulated macrophages, Atg16L1-deficiency causes Toll/IL-1 receptor domain-containing adaptor inducing IFN-beta (TRIF)-dependent activation of caspase-1, leading to increased production of IL-1beta. Mice lacking Atg16L1 in haematopoietic cells are highly susceptible to dextran sulphate sodium-induced acute colitis, which is alleviated by injection of anti-IL-1beta and IL-18 antibodies, indicating the importance of Atg16L1 in the suppression of intestinal inflammation. These results demonstrate that Atg16L1 is an essential component of the autophagic machinery responsible for control of the endotoxin-induced inflammatory immune response.     

An X-ray-emitting blast wave from the recurrent nova RS Ophiuchi

Stellar explosions such as novae and supernovae produce most of the heavy elements in the Universe. The onset of a nova is well understood as driven by runaway thermonuclear fusion reactions on the surface of a white dwarf in a binary star system; but the structure, dynamics and mass of the ejecta are not well known. In rare cases, the white dwarf is embedded in the wind nebula of a red-giant companion, and the explosion products plough through the nebula and produce X-ray emission. Here we report X-ray observations of such an event, from the eruption of the recurrent nova RS Ophiuchi. The hard X-ray emission from RS Ophiuchi early in the eruption emanates from behind a blast wave, or outward-moving shock wave, that expanded freely for less than 2 days and then decelerated owing to interaction with the nebula. The X-rays faded rapidly, suggesting that the blast wave deviates from the standard spherical shell structure. The early onset of deceleration indicates that the ejected shell had a low mass, the white dwarf has a high mass, and that RS Ophiuchi is therefore a progenitor of the type of supernova (type Ia) integral to studies of the expansion of the Universe.