Targeting the deubiquitinase STAMBP inhibits NALP7 inflammasome activity

Joseph S. Bednash, Nathaniel Weathington, James Londino, Mauricio Rojas, Dexter L. Gulick, Robert Fort, SeungHye Han, Alison C. McKelvey, Bill B. Chen and Rama K. Mallampalli ()
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Joseph S. Bednash: Acute Lung Injury Center of Excellence, University of Pittsburgh, UPMC Montefiore
Nathaniel Weathington: Acute Lung Injury Center of Excellence, University of Pittsburgh, UPMC Montefiore
James Londino: Acute Lung Injury Center of Excellence, University of Pittsburgh, UPMC Montefiore
Mauricio Rojas: Acute Lung Injury Center of Excellence, University of Pittsburgh, UPMC Montefiore
Dexter L. Gulick: Acute Lung Injury Center of Excellence, University of Pittsburgh, UPMC Montefiore
Robert Fort: Acute Lung Injury Center of Excellence, University of Pittsburgh, UPMC Montefiore
SeungHye Han: Acute Lung Injury Center of Excellence, University of Pittsburgh, UPMC Montefiore
Alison C. McKelvey: Acute Lung Injury Center of Excellence, University of Pittsburgh, UPMC Montefiore
Bill B. Chen: Acute Lung Injury Center of Excellence, University of Pittsburgh, UPMC Montefiore
Rama K. Mallampalli: Acute Lung Injury Center of Excellence, University of Pittsburgh, UPMC Montefiore

Nature Communications, 2017, vol. 8, issue 1, 1-13

Abstract: Abstract Inflammasomes regulate innate immune responses by facilitating maturation of inflammatory cytokines, interleukin (IL)-1β and IL-18. NACHT, LRR and PYD domains-containing protein 7 (NALP7) is one inflammasome constituent, but little is known about its cellular handling. Here we show a mechanism for NALP7 protein stabilization and activation of the inflammasome by Toll-like receptor (TLR) agonism with bacterial lipopolysaccharide (LPS) and the synthetic acylated lipopeptide Pam3CSK4. NALP7 is constitutively ubiquitinated and recruited to the endolysosome for degradation. With TLR ligation, the deubiquitinase enzyme, STAM-binding protein (STAMBP) impedes NALP7 trafficking to lysosomes to increase NALP7 abundance. STAMBP deubiquitinates NALP7 and STAMBP knockdown abrogates LPS or Pam3CSK4-induced increases in NALP7 protein. A small-molecule inhibitor of STAMBP deubiquitinase activity, BC-1471, decreases NALP7 protein levels and suppresses IL-1β release after TLR agonism. These findings describe a unique pathway of inflammasome regulation with the identification of STAMBP as a potential therapeutic target to reduce pro-inflammatory stress.

Date: 2017
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DOI: 10.1038/ncomms15203

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