PMID- 17095513
OWN - NLM
STAT- MEDLINE
DCOM- 20070307
LR  - 20210209
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 282
IP  - 2
DP  - 2007 Jan 12
TI  - Execution of macrophage apoptosis by PE_PGRS33 of Mycobacterium tuberculosis is 
      mediated by Toll-like receptor 2-dependent release of tumor necrosis 
      factor-alpha.
PG  - 1039-50
AB  - Combating tuberculosis requires a detailed understanding of how mycobacterial 
      effectors modulate the host immune response. The role of the multigene PE family 
      of proteins unique to mycobacteria in the pathogenesis of tuberculosis is still 
      poorly understood, although certain PE_PGRS genes have been linked to virulence. 
      Tumor necrosis factor-alpha (TNF-alpha) is essential for successfully combating 
      tuberculosis. In this study we provide evidence that PE_PGRS33, a surface exposed 
      protein, elicits TNF-alpha release from macrophages in a TLR2 (Toll-like receptor 
      2)-dependent manner. ASK1 (apoptosis signal-regulating kinase 1) is activated 
      downstream of TLR2. ASK1 activates the MAPKs p38 and JNK. PE_PGRS33-induced 
      signaling leads to enhanced expression of TNF-alpha and TNF receptor I (TNFRI) 
      genes. Mycobacterium smegmatis expressing PE_ PGRS33 elicits the same effects as 
      purified PE_PGRS33. TNF-alpha release occurs even when internalization of the 
      bacteria is blocked by cytochalasin D, suggesting that interaction of PE_ PGRS33 
      with TLR2 is sufficient to trigger the effects described. Release of TNF-alpha 
      plays the determining role in triggering apoptosis in macrophages challenged with 
      PE_PGRS33. The death receptor-dependent signals are amplified through classical 
      caspase 8-dependent mitochondrial release of cytochrome c, leading to the 
      activation of caspases 9 and 3. An important aspect of our findings is that 
      deletions within the PGRS domain (simulating those occurring in clinical strains) 
      attenuate the TNF-alpha-inducing ability of PE_PGRS33. These results provide the 
      first evidence that variations in the polymorphic repeats of the PGRS domain 
      modulate the innate immune response.
FAU - Basu, Sanchita
AU  - Basu S
AD  - Department of Chemistry, Bose Institute, 93/1 Acharya Prafulla Chandra Road, 
      Kolkata 700009, India.
FAU - Pathak, Sushil Kumar
AU  - Pathak SK
FAU - Banerjee, Anirban
AU  - Banerjee A
FAU - Pathak, Shresh
AU  - Pathak S
FAU - Bhattacharyya, Asima
AU  - Bhattacharyya A
FAU - Yang, Zhenhua
AU  - Yang Z
FAU - Talarico, Sarah
AU  - Talarico S
FAU - Kundu, Manikuntala
AU  - Kundu M
FAU - Basu, Joyoti
AU  - Basu J
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20061109
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Antigens, Bacterial)
RN  - 0 (Bacterial Proteins)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (Membrane Proteins)
RN  - 0 (PE-PGRS protein, Mycobacterium)
RN  - 0 (Receptors, Death Domain)
RN  - 0 (Recombinant Proteins)
RN  - 0 (TLR2 protein, human)
RN  - 0 (Toll-Like Receptor 2)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases)
RN  - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
RN  - EC 2.7.11.25 (MAP Kinase Kinase Kinase 5)
RN  - EC 2.7.11.25 (Map3k5 protein, mouse)
RN  - EC 3.4.22.- (Caspase 8)
SB  - IM
MH  - Animals
MH  - Antigens, Bacterial/*genetics/pharmacology
MH  - Apoptosis/immunology
MH  - Bacterial Proteins/*genetics/pharmacology
MH  - Caspase 8/metabolism
MH  - Cell Line
MH  - Gene Deletion
MH  - Humans
MH  - JNK Mitogen-Activated Protein Kinases/metabolism
MH  - Kidney/cytology
MH  - Lipopolysaccharides
MH  - MAP Kinase Kinase Kinase 5/metabolism
MH  - MAP Kinase Signaling System/drug effects/immunology
MH  - Macrophages/*cytology/metabolism/microbiology
MH  - Membrane Proteins/*genetics/pharmacology
MH  - Mice
MH  - Mitochondria/physiology
MH  - Mutagenesis
MH  - Mycobacterium smegmatis/genetics
MH  - Mycobacterium tuberculosis/*genetics
MH  - Polymorphism, Genetic
MH  - Receptors, Death Domain/metabolism
MH  - Recombinant Proteins/pharmacology
MH  - Toll-Like Receptor 2/*metabolism
MH  - Tuberculosis/*immunology/physiopathology
MH  - Tumor Necrosis Factor-alpha/genetics/*metabolism
MH  - p38 Mitogen-Activated Protein Kinases/metabolism
EDAT- 2006/11/11 09:00
MHDA- 2007/03/08 09:00
CRDT- 2006/11/11 09:00
PHST- 2006/11/11 09:00 [pubmed]
PHST- 2007/03/08 09:00 [medline]
PHST- 2006/11/11 09:00 [entrez]
AID - S0021-9258(20)73530-1 [pii]
AID - 10.1074/jbc.M604379200 [doi]
PST - ppublish
SO  - J Biol Chem. 2007 Jan 12;282(2):1039-50. doi: 10.1074/jbc.M604379200. Epub 2006 
      Nov 9.