LRRK2 promotes the activation of NLRC4 inflammasome during Salmonella Typhimurium infection

Although genetic polymorphisms in the LRRK2 gene are associated with a variety of diseases, the physiological function of LRRK2 remains poorly understood. In this study, we report a crucial role for LRRK2 in the activation of the NLRC4 inflammasome during host defense against Salmonella enteric serovar Typhimurium infection. LRRK2 deficiency reduced caspase-1 activation and IL-1&bgr; secretion in response to NLRC4 inflammasome activators in macrophages. Lrrk2−/− mice exhibited impaired clearance of pathogens after acute S. Typhimurium infection. Mechanistically, LRRK2 formed a complex with NLRC4 in the macrophages, and the formation of the LRRK2–NLRC4 complex led to the phosphorylation of NLRC4 at Ser533. Importantly, the kinase activity of LRRK2 is required for optimal NLRC4 inflammasome activation. Collectively, our study reveals an important role for LRRK2 in the host defense by promoting NLRC4 inflammasome activation.

• Publication year

  2017

• Venue

  Journal of Experimental Medicine

• Publication date

  2017-10-02

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1084/jem.20170014PMID 28821568PMCID 5626397
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• LRRK2 kinase activity is required for optimal NLRC4 inflammasome activation.

  Confidence 0.95

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewB (s683577b42) reviewAK (4715169a40) review
• LRRK2 forms a complex with NLRC4 in macrophages, and this association is linked to phosphorylation of NLRC4 at Ser533.

  Confidence 0.96

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewB (s683577b42) reviewAK (4715169a40) review
• Lrrk2-/- mice show impaired pathogen clearance after acute Salmonella Typhimurium infection.

  Confidence 0.97

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewB (s683577b42) reviewAK (4715169a40) review
• LRRK2 deficiency reduces caspase-1 activation and IL-1β secretion in macrophages responding to NLRC4 inflammasome activators.

  Confidence 0.98

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewB (s683577b42) reviewAK (4715169a40) review

• caspase-1 activation

  molecular event, biochemical process

  The activated state of caspase-1 used as a readout of inflammasome signaling.

  Aliases: caspase-1 cleavage

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewB (s683577b42) reviewAK (4715169a40) review
• il-1β secretion

  cytokine release, immune response

  Release of the pro-inflammatory cytokine IL-1beta from stimulated cells.

  Aliases: interleukin-1beta secretion, IL-1 beta secretion

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewB (s683577b42) reviewAK (4715169a40) review
• lrrk2

  protein, kinase

  A leucine-rich repeat kinase 2 protein studied here in macrophage inflammasome signaling and host defense.

  Aliases: leucine-rich repeat kinase 2

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewB (s683577b42) reviewAK (4715169a40) review
• lrrk2 kinase activity

  enzymatic activity, molecular function

  The enzymatic activity of LRRK2 that enables phosphorylation-dependent signaling.

  Aliases: LRRK2 enzymatic activity

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewB (s683577b42) reviewAK (4715169a40) review
• macrophages

  cell type, immune cell

  Innate immune cells used as the primary cellular system for testing inflammasome responses.

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewB (s683577b42) reviewAK (4715169a40) review
• nlrc4 inflammasome

  protein complex, innate immune complex

  An NLRC4-centered inflammasome complex involved in innate immune activation and caspase-1 signaling.

  Aliases: NLRC4 inflammasome complex

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewB (s683577b42) reviewAK (4715169a40) review
• nlrc4 ser533 phosphorylation

  post-translational modification, molecular event

  Phosphorylation of NLRC4 at the serine 533 residue, a specific post-translational modification mentioned in the abstract.

  Aliases: NLRC4 phosphorylation at Ser533, phosphorylated NLRC4 Ser533

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewB (s683577b42) reviewAK (4715169a40) review
• pathogen clearance

  outcome, host defense outcome

  Removal or reduction of infectious bacteria from the host during infection.

  Aliases: clearance of pathogens

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewB (s683577b42) reviewAK (4715169a40) review
• salmonella typhimurium infection

  infection, disease model

  An acute bacterial infection model using Salmonella enterica serovar Typhimurium in mice.

  Aliases: S. Typhimurium infection, Salmonella enterica serovar Typhimurium infection

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewB (s683577b42) reviewAK (4715169a40) review

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