Targeting the deubiquitinase STAMBP inhibits NALP7 inflammasome activity

被引：51

作者：

Bednash, Joseph S. ^{[1
]}

Weathington, Nathaniel ^{[1
]}

Londino, James ^{[1
]}

Rojas, Mauricio ^{[1
]}

Gulick, Dexter L. ^{[1
]}

Fort, Robert ^{[1
]}

Han, SeungHye ^{[1
]}

McKelvey, Alison C. ^{[1
]}

Chen, Bill B. ^{[1
]}

Mallampalli, Rama K. ^{[1
,2
,3
,4
]}

机构：

[1] Univ Pittsburgh, UPMC Montefiore, Acute Lung Injury Ctr Excellence, Dept Med, NW 628, Pittsburgh, PA 15213 USA

[2] Univ Pittsburgh, Dept Cell Biol & Physiol, Pittsburgh, PA 15213 USA

[3] Univ Pittsburgh, Dept Bioengn, Pittsburgh, PA 15213 USA

[4] Vet Affairs Pittsburgh Healthcare Syst, Med Specialty Serv Line, Pittsburgh, PA 15240 USA

来源：

NATURE COMMUNICATIONS | 2017年 / 8卷

基金：

美国国家卫生研究院;

关键词：

NLRP3; INFLAMMASOME; UBIQUITIN ISOPEPTIDASE; RECEPTOR DEGRADATION; E3; LIGASE; ACTIVATION; PROTEIN; DOMAIN; AMSH; DISEASE; STABILITY;

D O I：

10.1038/ncomms15203

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Inflammasomes regulate innate immune responses by facilitating maturation of inflammatory cytokines, interleukin (IL)-1 beta 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-1 beta 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.

引用

页数：13

共 52 条

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