title: Human leucine-rich repeat proteins: a genome-wide bioinformatic categorization and functional analysis in innate immunity.
abstract: In innate immune sensing, the detection of pathogen-associated molecular patterns by recognition receptors typically involve leucine-rich repeats (LRRs). We provide a categorization of 375 human LRR-containing proteins, almost half of which lack other identifiable functional domains. We clustered human LRR proteins by first assigning LRRs to LRR classes and then grouping the proteins based on these class assignments, revealing several of the resulting protein groups containing a large number of proteins with certain non-LRR functional domains. In particular, a statistically significant number of LRR proteins in the typical (T) and bacterial + typical (S+T) categories have transmembrane domains, whereas most of the LRR proteins in the cysteine-containing (CC) category contain an F-box domain (which mediates interactions with the E3 ubiquitin ligase complex). Furthermore, by examining the evolutionary profiles of the LRR proteins, we identified a subset of LRR proteins exhibiting strong conservation in fungi and an enrichment for "nucleic acid-binding" function. Expression analysis of LRR genes identifies a subset of pathogen-responsive genes in human primary macrophages infected with pathogenic bacteria. Using functional RNAi, we show that MFHAS1 regulates Toll-like receptor (TLR)-dependent signaling. By using protein interaction network analysis followed by functional RNAi, we identified LRSAM1 as a component of the antibacterial autophagic response.
authors.affiliation: Center for Computational and Integrative Biology, and Gastrointestinal Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Aylwin C Y
authors.initials: AC
authors.lastname: Ng
authors.forename: Jason M
authors.initials: JM
authors.lastname: Eisenberg
authors.forename: Robert J W
authors.initials: RJ
authors.lastname: Heath
authors.forename: Alan
authors.initials: A
authors.lastname: Huett
authors.forename: Cory M
authors.initials: CM
authors.lastname: Robinson
authors.forename: Gerard J
authors.initials: GJ
authors.lastname: Nau
authors.forename: Ramnik J
authors.initials: RJ
authors.lastname: Xavier
mesh_terms: D018797:Cell Cycle Proteins / Q000378:metabolism*; D016000:Cluster Analysis; D019295:Computational Biology / Q000379:methods; D004268:DNA-Binding Proteins / Q000378:metabolism*; D019143:Evolution, Molecular; D020869:Gene Expression Profiling; D055106:Genome-Wide Association Study; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics* / Q000276:immunology; D000090263:Leucine-Rich Repeat Proteins; D008264:Macrophages / Q000378:metabolism / Q000382:microbiology; D015513:Oncogene Proteins / Q000378:metabolism*; D011506:Proteins / Q000145:classification / Q000235:genetics* / Q000276:immunology*; D034622:RNA Interference; D015398:Signal Transduction / Q000235:genetics*; D051193:Toll-Like Receptors / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D000090263:Leucine-Rich Repeat Proteins; C117302:MFHAS1 protein, human; D015513:Oncogene Proteins; D011506:Proteins; D051193:Toll-Like Receptors