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; Rama K. Mallampalli

doi:10.1038/ncomms15203

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, Rama K. Mallampalli^*

^*Corresponding author for this work

Medicine, Pulmonary Division

Research output: Contribution to journal › Article › peer-review

57 Scopus citations

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-1b 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.

Original language	English (US)
Article number	15203
Journal	Nature communications
Volume	8
DOIs	https://doi.org/10.1038/ncomms15203
State	Published - 2017

Funding

This material is based upon work supported, in part, by the US Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development. This work was supported by a Merit Review Award from the US Department of Veterans Affairs and National Institutes of Health R01 grants HL096376, HL097376, HL098174, HL081784, 1UH2HL123502, P01HL114453 and the Flight Attendant Medical Research Institute (to R.K.M.), and by the National Institutes of Health R01 grant HL116472 and HL132862 (to B.B.C.). The contents presented do not represent the views of the Department of Veterans Affairs or the United States Government. Microscopy was supported by Claudette M. St Croix and Mark Ross of the Center for Biological Imaging at the University of Pittsburgh.

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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title = "Targeting the deubiquitinase STAMBP inhibits NALP7 inflammasome activity",

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-1b 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.",

author = "Bednash, {Joseph S.} and Nathaniel Weathington and James Londino and Mauricio Rojas and Gulick, {Dexter L.} and Robert Fort and SeungHye Han and McKelvey, {Alison C.} and Chen, {Bill B.} and Mallampalli, {Rama K.}",

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AU - Bednash, Joseph S.

AU - Weathington, Nathaniel

AU - Londino, James

AU - Rojas, Mauricio

AU - Gulick, Dexter L.

AU - Fort, Robert

AU - Han, SeungHye

AU - McKelvey, Alison C.

AU - Chen, Bill B.

AU - Mallampalli, Rama K.

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AB - 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-1b 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.

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Targeting the deubiquitinase STAMBP inhibits NALP7 inflammasome activity

Abstract

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UN SDGs

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