title: NLRP4 negatively regulates autophagic processes through an association with beclin1.
abstract: Although more than 20 putative members have been assigned to the nucleotide-binding and oligomerization domain-like receptor (NLR) family, their physiological and biological roles, with the exception of the inflammasome, are not fully understood. In this article, we show that NLR members, such as NLRC4, NLRP3, NLRP4, and NLRP10 interact with Beclin1, an important regulator of autophagy, through their neuronal apoptosis inhibitory protein, MHC class II transcription activator, incompatibility locus protein from Podospora anserina, and telomerase-associated protein domain. Among such NLRs, NLRP4 had a strong affinity to the Beclin1 evolutionally conserved domain. Compromising NLRP4 via RNA interference resulted in upregulation of the autophagic process under physiological conditions and upon invasive bacterial infections, leading to enhancement of the autophagic bactericidal process of group A streptococcus. NLRP4 recruited to the subplasma membrane phagosomes containing group A streptococcus and transiently dissociated from Beclin1, suggesting that NLRP4 senses bacterial infection and permits the initiation of Beclin1-mediated autophagic responses. In addition to a role as a negative regulator of the autophagic process, NLRP4 physically associates with the class C vacuolar protein-sorting complex, thereby negatively regulating maturation of the autophagosome and endosome. Collectively, these results provide novel evidence that NLRP4, and possibly other members of the NLR family, plays a crucial role in biogenesis of the autophagosome and its maturation by the association with regulatory molecules, such as Beclin1 and the class C vacuolar protein-sorting complex.
authors.affiliation: Department of Molecular Biodefense Research, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
authors.forename: Nao
authors.initials: N
authors.lastname: Jounai
authors.forename: Kouji
authors.initials: K
authors.lastname: Kobiyama
authors.forename: Masaaki
authors.initials: M
authors.lastname: Shiina
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Ogata
authors.forename: Ken J
authors.initials: KJ
authors.lastname: Ishii
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Takeshita
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism / Q000502:physiology*; D001343:Autophagy / Q000276:immunology*; D000071186:Beclin-1; D001770:Blood Bactericidal Activity / Q000276:immunology; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000276:immunology*; D024881:Drug Resistance, Bacterial / Q000276:immunology*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008247:Lysosomes / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D008565:Membrane Proteins / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D010588:Phagosomes / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D013290:Streptococcal Infections / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D013297:Streptococcus pyogenes / Q000276:immunology; D014617:Vacuoles / Q000276:immunology / Q000382:microbiology / Q000473:pathology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D008565:Membrane Proteins; C466775:NLRP4 protein, human; D012097:Repressor Proteins