PMID- 34324582
OWN - NLM
STAT- MEDLINE
DCOM- 20211021
LR  - 20221130
IS  - 1553-7374 (Electronic)
IS  - 1553-7366 (Print)
IS  - 1553-7366 (Linking)
VI  - 17
IP  - 7
DP  - 2021 Jul
TI  - Mycobacterium tuberculosis inhibits the NLRP3 inflammasome activation via its 
      phosphokinase PknF.
PG  - e1009712
LID - 10.1371/journal.ppat.1009712 [doi]
LID - e1009712
AB  - Mycobacterium tuberculosis (Mtb) has evolved to evade host innate immunity by 
      interfering with macrophage functions. Interleukin-1beta (IL-1beta) is secreted by 
      macrophages after the activation of the inflammasome complex and is crucial for 
      host defense against Mtb infections. We have previously shown that Mtb is able to 
      inhibit activation of the AIM2 inflammasome and subsequent pyroptosis. Here we 
      show that Mtb is also able to inhibit host cell NLRP3 inflammasome activation and 
      pyroptosis. We identified the serine/threonine kinase PknF as one protein of Mtb 
      involved in the NLRP3 inflammasome inhibition, since the pknF deletion mutant of 
      Mtb induces increased production of IL-1beta in bone marrow-derived macrophages 
      (BMDMs). The increased production of IL-1beta was dependent on NLRP3, the adaptor 
      protein ASC and the protease caspase-1, as revealed by studies performed in 
      gene-deficient BMDMs. Additionally, infection of BMDMs with the pknF deletion 
      mutant resulted in increased pyroptosis, while the IL-6 production remained 
      unchanged compared to Mtb-infected cells, suggesting that the mutant did not 
      affect the priming step of inflammasome activation. In contrast, the activation 
      step was affected since potassium efflux, chloride efflux and the generation of 
      reactive oxygen species played a significant role in inflammasome activation and 
      subsequent pyroptosis mediated by the Mtb pknF mutant strain. In conclusion, we 
      reveal here that the serine/threonine kinase PknF of Mtb plays an important role 
      in innate immune evasion through inhibition of the NLRP3 inflammasome.
FAU - Rastogi, Shivangi
AU  - Rastogi S
AD  - Department of Cell Biology and Molecular Genetics, University of Maryland, 
      College Park, Maryland, United States of America.
FAU - Ellinwood, Sarah
AU  - Ellinwood S
AD  - Department of Cell Biology and Molecular Genetics, University of Maryland, 
      College Park, Maryland, United States of America.
FAU - Augenstreich, Jacques
AU  - Augenstreich J
AUID- ORCID: 0000-0003-2147-2675
AD  - Department of Cell Biology and Molecular Genetics, University of Maryland, 
      College Park, Maryland, United States of America.
FAU - Mayer-Barber, Katrin D
AU  - Mayer-Barber KD
AUID- ORCID: 0000-0002-0311-3233
AD  - Inflammation and Innate Immunity Unit, Laboratory of Clinical Immunology and 
      Microbiology, National Institute of Allergy and Infectious Diseases, National 
      Institutes of Health, Bethesda, Maryland, United States of America.
FAU - Briken, Volker
AU  - Briken V
AUID- ORCID: 0000-0001-5830-6107
AD  - Department of Cell Biology and Molecular Genetics, University of Maryland, 
      College Park, Maryland, United States of America.
LA  - eng
GR  - R01 AI147630/AI/NIAID NIH HHS/United States
GR  - S10 OD025223/OD/NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20210729
PL  - United States
TA  - PLoS Pathog
JT  - PLoS pathogens
JID - 101238921
RN  - 0 (Inflammasomes)
RN  - 0 (NLR Family, Pyrin Domain-Containing 3 Protein)
RN  - EC 2.7.11.1 (PknF protein, Mycobacterium tuberculosis)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
SB  - IM
MH  - Animals
MH  - Host-Pathogen Interactions/immunology
MH  - Immune Evasion/*immunology
MH  - Inflammasomes/*immunology
MH  - Mice
MH  - Mycobacterium tuberculosis/*immunology/metabolism
MH  - NLR Family, Pyrin Domain-Containing 3 Protein/*immunology
MH  - Protein Serine-Threonine Kinases/*immunology/metabolism
MH  - Tuberculosis/*immunology/metabolism
PMC - PMC8321130
COIS- The authors have declared that no competing interests exist.
EDAT- 2021/07/30 06:00
MHDA- 2022/04/15 06:00
PMCR- 2021/07/29
CRDT- 2021/07/29 17:29
PHST- 2021/01/05 00:00 [received]
PHST- 2021/06/14 00:00 [accepted]
PHST- 2021/07/29 17:29 [entrez]
PHST- 2021/07/30 06:00 [pubmed]
PHST- 2022/04/15 06:00 [medline]
PHST- 2021/07/29 00:00 [pmc-release]
AID - PPATHOGENS-D-21-00033 [pii]
AID - 10.1371/journal.ppat.1009712 [doi]
PST - epublish
SO  - PLoS Pathog. 2021 Jul 29;17(7):e1009712. doi: 10.1371/journal.ppat.1009712. 
      eCollection 2021 Jul.