Abstract
The mammalian NLR gene family was first reported over 20 years ago, although several genes that were later grouped into the family were already known at that time. Although it is widely known that NLRs include inflammasome receptors and/or sensors that promote the maturation of caspase 1, IL-1β, IL-18 and gasdermin D to drive inflammation and cell death, the other functions of NLR family members are less well appreciated by the scientific community. Examples include MHC class II transactivator (CIITA), a master transcriptional activator of MHC class II genes, which was the first mammalian NBD–LRR-containing protein to be identified, and NLRC5, which regulates the expression of MHC class I genes. Other NLRs govern key inflammatory signalling pathways or interferon responses, and several NLR family members serve as negative regulators of innate immune responses. Multiple NLRs regulate the balance of cell death, cell survival, autophagy, mitophagy and even cellular metabolism. Perhaps the least discussed group of NLRs are those with functions in the mammalian reproductive system. The focus of this Review is to provide a synopsis of the NLR family, including both the intensively studied and the underappreciated members. We focus on the function, structure and disease relevance of NLRs and highlight issues that have received less attention in the NLR field. We hope this may serve as an impetus for future research on the conventional and non-conventional roles of NLRs within and beyond the immune system.
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Change history
17 May 2023
A Correction to this paper has been published: https://doi.org/10.1038/s41577-023-00891-9
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Acknowledgements
This work is supported by NIH grants R56 AI158314, R01 AI158314, AI029564, AI141333, DK094779, U19 AI067798 and R35 CA232109 to J.P.-Y.T.
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J.P-Y.T. is a co-founder of IMMvention Therapeutix. The other authors declare no competing interests.
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Related links
Walker A and Walker B motifs: https://en.wikipedia.org/wiki/Walker_motifs
Glossary
- AIM2
-
An innate immune sensor that detects cytosolic double-stranded DNA, resulting in inflammasome formation. AIM2 is composed of an N-terminal pyrin domain (PYD) and a C-terminal double-stranded DNA-binding HIN domain distinguishing it from NLR inflammasome proteins.
- Anakinra
-
A short-acting human recombinant IL-1 receptor (IL-1R) antagonist that can competitively inhibit the binding of IL-1β and IL-1α to IL-1R and block IL-1 signal transduction.
- APAF1
-
A protein of the STAND class of P-loop ATPases that is central to initiating apoptosis upon mitochondrial cytochrome c release into the cytosol. In addition to the STAND ATPase module, APAF1 contains an N-terminal caspase recruitment domain (CARD) and C-terminal WD40 repeats. The formation of the apoptosome and activation of caspase 9 upon cytochrome c binding was a biochemical model that significantly influenced early NLR studies.
- ASC
-
(Also known as PYCARD and TMS1). Adaptor protein that contains a pyrin domain (PYD) and caspase recruitment domain (CARD) allowing for inflammasome recruitment of pro-caspase 1.
- Cryopyrin-induced autoinflammatory syndromes
-
(CAPS). Autoinflammatory diseases caused by gain-of-function mutations in NLRP3 (cryopyrin).
- Hydatidiform moles
-
A hydatidiform mole is a rare condition in which tissue around a fertilized egg that would normally have developed into the placenta instead develops as an abnormal mass of cells.
- Imprinting disorder
-
Diseases caused by genetic defects or epigenetic mutations affecting imprinted chromosomal regions or genes that are expressed in a parent-of-origin specific manner.
- Inflammasomopathies
-
Autoinflammatory diseases resulting from gain-of-function mutations in inflammasome-forming NLRs.
- Maternal-effect genes
-
Genes that are transcribed in the mother and influence the development of oocytes and embryos.
- MHC class II transactivator
-
(CIITA). The master transcriptional regulator of MHC class II expression.
- M2-like macrophages
-
M1 and M2 are classifications historically used to define macrophages activated in vitro as pro-inflammatory or anti-inflammatory, respectively. In vivo macrophages are highly specialized, transcriptomically dynamic and extremely heterogeneous. Therefore, the M1 or M2 classification is too simplistic to explain the true nature of in vivo macrophages, but these terms are still often used to indicate whether the macrophages in question are more pro-inflammatory or anti-inflammatory.
- NACHT domain
-
The NACHT domain is a subgroup of the STAND class of P-loop NTPases and is composed of four subdomains (NBD, HD1, WHD and HD2). This domain allows for nucleotide-binding-dependent conformational changes and oligomerization to influence diverse biological outcomes such as transcriptional activation, cytokine signalling and pyroptosis.
- NR100
-
N-terminal domain of rodent NLRP1 proteins, approximately 100 amino acids. Whereas human NLRP1 possesses an N-terminal PYD, mouse NLRP1 proteins contain this sequence of unknown function. AlphaFold predicts this region to be mostly disordered.
- STAND
-
A subgroup of the AAA+ ATPase superfamily that includes both apoptotic ATPases as well as NACHT ATPases. The model for STAND protein function involves ADP binding stabilizing a closed, inactive state, and exchange for ATP triggers a conformational change to the open, active state.
- SXY cis-elements
-
A regulatory module comprising four elements: S or W box, X1 box, X2 box, and the Y box. When bound by their cognate transcription factors, these sites allow for assembly of the MHC enhanceosome.
- Type III secretion system
-
(T3SS). A multiprotein membrane apparatus present in Gram-negative bacteria used to inject proteins into host cytosol. Components of this nanomachine trigger NAIP–NLRC4 inflammasome assembly.
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Chou, WC., Jha, S., Linhoff, M.W. et al. The NLR gene family: from discovery to present day. Nat Rev Immunol 23, 635–654 (2023). https://doi.org/10.1038/s41577-023-00849-x
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DOI: https://doi.org/10.1038/s41577-023-00849-x
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