Abstract
The ability to control the timing and mode of host cell death plays a pivotal role in microbial infections. Many bacteria use toxins to kill host cells and evade immune responses. Such toxins are unknown in Mycobacterium tuberculosis. Virulent M. tuberculosis strains induce necrotic cell death in macrophages by an obscure molecular mechanism. Here we show that the M. tuberculosis protein Rv3903c (channel protein with necrosis-inducing toxin, CpnT) consists of an N-terminal channel domain that is used for uptake of nutrients across the outer membrane and a secreted toxic C-terminal domain. Infection experiments revealed that CpnT is required for survival and cytotoxicity of M. tuberculosis in macrophages. Furthermore, we demonstrate that the C-terminal domain of CpnT causes necrotic cell death in eukaryotic cells. Thus, CpnT has a dual function in uptake of nutrients and induction of host cell death by M. tuberculosis.
Keywords:
pore; secretion; transport.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Amino Acid Sequence
-
Animals
-
Bacterial Outer Membrane Proteins / chemistry
-
Bacterial Outer Membrane Proteins / genetics
-
Bacterial Outer Membrane Proteins / metabolism*
-
Bacterial Toxins / chemistry
-
Bacterial Toxins / genetics
-
Bacterial Toxins / metabolism*
-
Cell Line
-
Exotoxins / chemistry
-
Exotoxins / genetics
-
Exotoxins / metabolism*
-
Genes, Bacterial
-
Glycerol / metabolism
-
HEK293 Cells
-
Humans
-
Jurkat Cells
-
Macrophages / microbiology
-
Mice
-
Mice, Inbred C57BL
-
Molecular Sequence Data
-
Mutation
-
Mycobacterium bovis / genetics
-
Mycobacterium bovis / growth & development
-
Mycobacterium bovis / metabolism
-
Mycobacterium tuberculosis / genetics
-
Mycobacterium tuberculosis / metabolism*
-
Mycobacterium tuberculosis / pathogenicity
-
Phylogeny
-
Protein Structure, Tertiary
-
Recombinant Proteins / genetics
-
Recombinant Proteins / toxicity
-
Sequence Homology, Amino Acid
-
Virulence / genetics
-
Virulence / physiology
Substances
-
Bacterial Outer Membrane Proteins
-
Bacterial Toxins
-
Exotoxins
-
Recombinant Proteins
-
Rv3903 protein, Mycobacterium tuberculosis
-
Glycerol