Universität zu Köln

Huang, Menghang, Zhang, Xiaoxiao ORCID: 0000-0003-3762-2287, Toh, Gee Ann ORCID: 0000-0002-7417-8376, Gong, Qin, Wang, Jia, Han, Zhifu, Wu, Bin, Zhong, Franklin and Chai, Jijie ORCID: 0000-0001-7591-3873 (2021). Structural and biochemical mechanisms of NLRP1 inhibition by DPP9. Nature, 592 (7856). S. 773 - 797. BERLIN: NATURE RESEARCH. ISSN 1476-4687

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Abstract

Nucleotide-binding domain, leucine-rich repeat receptors (NLRs) mediate innate immunity by forming inflammasomes. Activation of the NLR protein NLRP1 requires autocleavage within its function-to-find domain (FIIND)(1-7). In resting cells, the dipeptidyl peptidases DPP8 and DPP9 interact with the FIIND of NLRP1 and suppress spontaneous NLRP1 activation(8,9); however, the mechanisms through which this occurs remain unknown. Here we present structural and biochemical evidence that full-length rat NLRP1 (rNLRP1) and rat DPP9 (rDPP9) form a 2:1 complex that contains an autoinhibited rNLRP1 molecule and an active UPA-CARD fragment of rNLRP1. The ZU5 domain is required not only for autoinhibition of rNLRP1 but also for assembly of the 2:1 complex. Formation of the complex prevents UPA-mediated higher-order oligomerization of UPA-CARD fragments and strengthens ZU5-mediated NLRP1 autoinhibition. Structure-guided biochemical and functional assays show that both NLRP1 binding and enzymatic activity are required for DPP9 to suppress NLRP1 in human cells. Together, our data reveal the mechanism of DPP9-mediated inhibition of NLRP1 and shed light on the activation of the NLRP1 inflammasome.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Huang, Menghang UNSPECIFIED UNSPECIFIED UNSPECIFIED Zhang, Xiaoxiao UNSPECIFIED orcid.org/0000-0003-3762-2287 UNSPECIFIED Toh, Gee Ann UNSPECIFIED orcid.org/0000-0002-7417-8376 UNSPECIFIED Gong, Qin UNSPECIFIED UNSPECIFIED UNSPECIFIED Wang, Jia UNSPECIFIED UNSPECIFIED UNSPECIFIED Han, Zhifu UNSPECIFIED UNSPECIFIED UNSPECIFIED Wu, Bin UNSPECIFIED UNSPECIFIED UNSPECIFIED Zhong, Franklin UNSPECIFIED UNSPECIFIED UNSPECIFIED Chai, Jijie UNSPECIFIED orcid.org/0000-0001-7591-3873 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-590225
DOI:	10.1038/s41586-021-03320-w
Journal or Publication Title:	Nature
Volume:	592
Number:	7856
Page Range:	S. 773 - 797
Date:	2021
Publisher:	NATURE RESEARCH
Place of Publication:	BERLIN
ISSN:	1476-4687
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language INFLAMMASOME; DOMAIN; FAMILY; FIIND Multiple languages Multidisciplinary Sciences Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/59022