IRGM Is a Common Target of RNA Viruses that Subvert the Autophagy Network

Autophagy is a conserved degradative pathway used as a host defense mechanism against intracellular pathogens. However, several viruses can evade or subvert autophagy to insure their own replication. Nevertheless, the molecular details of viral interaction with autophagy remain largely unknown. We have determined the ability of 83 proteins of several families of RNA viruses (Paramyxoviridae, Flaviviridae, Orthomyxoviridae, Retroviridae and Togaviridae), to interact with 44 human autophagy-associated proteins using yeast two-hybrid and bioinformatic analysis. We found that the autophagy network is highly targeted by RNA viruses. Although central to autophagy, targeted proteins have also a high number of connections with proteins of other cellular functions. Interestingly, immunity-associated GTPase family M (IRGM), the most targeted protein, was found to interact with the autophagy-associated proteins ATG5, ATG10, MAP1CL3C and SH3GLB1. Strikingly, reduction of IRGM expression using small interfering RNA impairs both Measles virus (MeV), Hepatitis C virus (HCV) and human immunodeficiency virus-1 (HIV-1)-induced autophagy and viral particle production. Moreover we found that the expression of IRGM-interacting MeV-C, HCV-NS3 or HIV-NEF proteins per se is sufficient to induce autophagy, through an IRGM dependent pathway. Our work reveals an unexpected role of IRGM in virus-induced autophagy and suggests that several different families of RNA viruses may use common strategies to manipulate autophagy to improve viral infectivity

Geometry effect on the estimation of band reflectance in an urban area

Reflectance of the urban surface is an important factor for urban climate studies and can be assessed using standard remote sensing applications. However, no application considers the three-dimensional structure of the city surface and its resulting shading patterns or the inclined roof surfaces. To determine the effect of these factors on the estimation of urban surface reflectance, a high-resolution raster-based city-surface model was used to estimate the spatial solar irradiance in an example city, namely Basel in Switzerland. Eight times daily for 1 year, the solar irradiance was calculated using MODTRAN and the illumination geometry of the city. Subsequently, the spatial distribution of the solar irradiance, as well as the error in assumed reflectance values were analysed. The error in estimation of reflectance increased with lower solar-elevation angle, so its maxima were found in winter.Higher visibility of the assumed atmosphere also increased the estimated error due to the lower proportion of diffuseirradiance. The error decreased with coarser spatial resolution of the pixel

Analysis of the combined action of miR-143 and miR-145 on oncogenic pathways in colorectal cancer cells reveals a coordinate program of gene repression

n/

Inflammatory bowel disease: dysfunction of autophagy?

Recent genome-wide association studies identified single nucleotide polymorphisms within gene loci, encoding autophagy genes, e.g. the autophagy-related 16-like 1 (ATG16L1) and the immunity-related GTPase family M (IRGM), as an important risk factor for the onset of chronic inflammatory diseases such as Crohn's disease (CD) or rheumatoid arthritis. CD is characterized by a breakdown of the intestinal epithelial barrier function leading to an overwhelming and uncontrolled immune response to bacterial antigens. Autophagy, and therefore ATG16L1 and IRGM, are critically involved in the innate immune response to invading pathogens. Dysfunction of these molecules results in the increased survival of intracellular bacteria, defective antigen presentation and proinflammatory cytokine secretion. Interestingly, autophagy can also be regulated by other CD susceptibility genes, such as nucleotide oligomerization domain 2 or protein tyrosine phosphatase nonreceptor type 2, and the presence of the CD-associated variations within these genes results in comparable effects. ATG16L1 also plays a crucial role in maintaining Paneth cell function and morphology, while IRGM seems to be associated with mitochondrial function and apoptosis. Dysfunction of these molecules, i.e. of autophagy in vivo, is clearly associated with the increased bacterial infection and the onset of colitis. Interestingly, the phenotype of aberrant Paneth cells and dextran sodium sulphate-induced colitis in ATG16L1 hypomorphic mice closely resembles human CD. Taken together, the available data strongly suggest an important role for autophagy in maintaining intestinal homeostasis, and dysfunction of autophagy seems to be a major risk factor for the onset of chronic intestinal inflammation