Allele-dependent interaction of LRRK2 and NOD2 in leprosy.
Journal
PLoS pathogens
ISSN: 1553-7374
Titre abrégé: PLoS Pathog
Pays: United States
ID NLM: 101238921
Informations de publication
Date de publication:
03 2023
03 2023
Historique:
received:
14
12
2022
accepted:
02
03
2023
revised:
06
04
2023
medline:
10
4
2023
pubmed:
28
3
2023
entrez:
27
3
2023
Statut:
epublish
Résumé
Leprosy, caused by Mycobacterium leprae, rarely affects children younger than 5 years. Here, we studied a multiplex leprosy family that included monozygotic twins aged 22 months suffering from paucibacillary leprosy. Whole genome sequencing identified three amino acid mutations previously associated with Crohn's disease and Parkinson's disease as candidate variants for early onset leprosy: LRRK2 N551K, R1398H and NOD2 R702W. In genome-edited macrophages, we demonstrated that cells expressing the LRRK2 mutations displayed reduced apoptosis activity following mycobacterial challenge independently of NOD2. However, employing co-immunoprecipitation and confocal microscopy we showed that LRRK2 and NOD2 proteins interacted in RAW cells and monocyte-derived macrophages, and that this interaction was substantially reduced for the NOD2 R702W mutation. Moreover, we observed a joint effect of LRRK2 and NOD2 variants on Bacillus Calmette-Guérin (BCG)-induced respiratory burst, NF-κB activation and cytokine/chemokine secretion with a strong impact for the genotypes found in the twins consistent with a role of the identified mutations in the development of early onset leprosy.
Identifiants
pubmed: 36972292
doi: 10.1371/journal.ppat.1011260
pii: PPATHOGENS-D-22-02170
pmc: PMC10079233
doi:
Substances chimiques
Nod2 Signaling Adaptor Protein
0
NOD2 protein, human
0
LRRK2 protein, human
EC 2.7.11.1
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
EC 2.7.11.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1011260Subventions
Organisme : CIHR
ID : FDN-143332
Pays : Canada
Informations de copyright
Copyright: © 2023 Dallmann-Sauer et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
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