The Nod-like receptor family member Naip5/Birc1e restricts Legionella pneumophila growth independently of caspase-1 activation.
Similar to Ipaf and caspase-1, the Nod-like receptor protein Naip5 restricts intracellular proliferation of Legionella pneumophila, the causative agent of a severe form of pneumonia known as Legionnaires' disease. Thus, Naip5 has been suggested to regulate Legionella replication inside macrophages through the activation of caspase-1. In this study, we show that cytosolic delivery of recombinant flagellin activated caspase-1 in A/J macrophages carrying a mutant Naip5 allele, and in C57BL/6 (B6) macrophages congenic for the mutant Naip5 allele (B6-Naip5(A/J)), but not in Ipaf(-/-) cells. In line with these results, A/J and B6-Naip5(A/J) macrophages induced high levels of caspase-1 activation and IL-1beta secretion when infected with Legionella. In addition, transgenic expression of a functional Naip5 allele in A/J macrophages did not alter Legionella-induced caspase-1 activation and IL-1beta secretion. Notably, defective Naip5 signaling renders B6-Naip5(A/J) macrophages permissive for Legionella proliferation despite normal caspase-1 activation. These results indicate that the restriction of intracellular Legionella replication is more complex than previously appreciated and requires both Ipaf-dependent caspase-1 activation as well as functional Naip5 signaling.
Lamkanfi
Mohamed
M
Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA.
Amer
Amal
A
Kanneganti
Thirumala-Devi
TD
Muñoz-Planillo
Raúl
R
Chen
Grace
G
Vandenabeele
Peter
P
Fortier
Anne
A
Gros
Philippe
P
Núñez
Gabriel
G
D000483:Alleles; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D020170:Caspase 1 / Q000378:metabolism*; D004789:Enzyme Activation; D005408:Flagellin / Q000494:pharmacology; D053583:Interleukin-1beta / Q000378:metabolism; D016952:Legionella pneumophila / Q000254:growth & development*; D007877:Legionnaires' Disease / Q000276:immunology* / Q000382:microbiology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology* / Q000382:microbiology; D051379:Mice; D020297:Mice, Congenic; D051616:Neuronal Apoptosis-Inhibitory Protein / Q000235:genetics / Q000502:physiology*; D021381:Protein Transport
D051017:Apoptosis Regulatory Proteins; D002135:Calcium-Binding Proteins; D053583:Interleukin-1beta; C512299:Ipaf protein, mouse; C496806:Naip5 protein, mouse; D051616:Neuronal Apoptosis-Inhibitory Protein; D005408:Flagellin; D020170:Caspase 1