the stehlik lab

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cytosolic pattern recognition receptor (PRR) biology

Nod-like receptor containing a PYD 7 (NLRP7; CLR19.4; HYDM; NALP7; NOD12; PAN7; PYPAF3)

 

We focus on basic mechanisms of innate immune sensing by cytosolic pattern recognition receptors of the Nod-like receptors (NLRs) and AIM2-like receptors (ALRs), which are involved in activation of inflammasomes, autophagy, type I interferons and NF-kB.  We discovered and characterized NLRC4 [1], NLRP4 [2], and co-discovered NLRP2 [3].  We recently discovered NLRP7 as an inflammasome activating PRR in human macrophages, using an RNAi screen [4].

 

NLRP7 senses bacterial lipopeptides, which requires its LRRs and hence, NLRP7 is crucial in eliminating infection by Gram positive bacteria, including Staphylococcus aureus and Listeria monocytogenes.  Upon infection, NLRP7 assembles into large protein complexes, which also contain ASC and caspase-1 and only these large complexes contain IL-1b maturating activity.  This oligomerization of NLRP7 requires its NACHT domain, which contains ATP binding and hydrolysis activities [5].

 

NLRP7 collaborates with TLR2 to promote IL-1b release, where TLR2 is necessary for inflammasome priming and NLRP7 for caspase-1 activation and cytokine release.  NLRP7 is one of the NLRs found in humans, but not in mice [6].  Hereditary mutations in NLRP7 are linked to hydatidiform mole (HM), which is a form of trophoblastic neoplasia characterized by cystic degeneration of the chorionic villi and abnormal or lack of embryonic growth and eventually develops into gestational choriocarcinoma, a highly aggressive cancer.  We demonstrated that several common HM-linked NLRP7 mutations show hyperactive inflammasome activation in vitro, raising the possibility that these mutations represent gain-of-function and that excessive inflammation may contribute to HM.  Studies to dissect the mechanism of NLRP7 inflammasome activation, function and signaling during inflammation and microbial infection are ongoing.

 

References

 

[1] *Damiano, J.S., *Stehlik, C., Pio, F., Godzik, A., and Reed, J.C. (2001) CLAN, a novel human CED4 like gene. Genomics 75, 77-83. *equally contributed

 

[2] *Fiorentino, L., *Stehlik, C. Oliveira, V., Ariza, M.E., Godzik, A., and Reed, J.C. (2002) A Novel PAAD-containing Protein That Modulates NF-kB Induction by Cytokines Tumor Necrosis Factor- and Interleukin-1. J. Biol. Chem. 277, 35333-35340. *equally contributed

 

[3] Bruey, J.M., Bruey-Sedano, N., Newman, R., Chandler, S., Stehlik, C., and Reed, J.C.  (2004) PAN1/NALP2/PYPAF2, an inducible inflammatory mediator that regulates NF-B and caspase-1 activation in macrophages. J. Biol. Chem. 279, 51897-51907

 

[4] Khare, S., Dorfleutner, A., Bryan, N.B., L., Yun, C., Radian, A.D., de Almeida, Rojanasakul, Y. and Stehlik, C. (2012) An NLRP7-containing inflammasome mediates recognition of microbial lipopeptides in macrophages. Immunity, 36, 464-476

 

[5] Radian, A.D., Khare, S, Dorfleutner, D. and Stehlik, C. (2015) ATP binding by NLRP7 is required for inflammasome activation in response to bacterial lipopeptides, Mol. Immunol., 2015, pii: S0161-5890(15)00437-X

 

[6] Radian, A.D., Dorfleutner, A., de Almeida, L., and Stehlik, C. (2013) NLRP7 and related inflammasome activating pattern recognition receptors and their function in host defense and disease. Microbes & Infection, 15, 630-639