RRC ID 34785
Author Jounai N, Kobiyama K, Shiina M, Ogata K, Ishii KJ, Takeshita F.
Title NLRP4 negatively regulates autophagic processes through an association with beclin1.
Journal J Immunol
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.
Volume 186(3)
Pages 1646-55
Published 2011-2-1
DOI 10.4049/jimmunol.1001654
PII jimmunol.1001654
PMID 21209283
MeSH Animals Apoptosis Regulatory Proteins / metabolism Apoptosis Regulatory Proteins / physiology* Autophagy / immunology* Beclin-1 Blood Bactericidal Activity / immunology Cell Line, Tumor Down-Regulation / immunology* Drug Resistance, Bacterial / immunology* HEK293 Cells HeLa Cells Humans Lysosomes / immunology Lysosomes / microbiology Lysosomes / pathology Membrane Proteins / metabolism Membrane Proteins / physiology* Mice Phagosomes / immunology Phagosomes / microbiology Phagosomes / pathology Protein Structure, Tertiary Protein Transport Repressor Proteins / antagonists & inhibitors Repressor Proteins / metabolism Repressor Proteins / physiology* Streptococcal Infections / immunology Streptococcal Infections / metabolism Streptococcal Infections / pathology Streptococcus pyogenes / immunology Vacuoles / immunology Vacuoles / microbiology Vacuoles / pathology
IF 4.718
Times Cited 102
DNA material pCAG-HIVgp (RDB04394) pCMV-VSV-G-RSV-Rev (RDB04393)