ACK1 and BRK non-receptor tyrosine kinase deficiencies are associated with familial systemic lupus and involved in efferocytosis Journal Article

   

Authors:	Guillet, S.; Lazarov, T.; Jordan, N.; Boisson, B.; Tello, M.; Craddock, B.; Zhou, T.; Nishi, C.; Bareja, R.; Yang, H.; Rieux-Laucat, F.; Fregel Lorenzo, R. I.; Dyall, S. D.; Isenberg, D.; D'Cruz, D.; Lachmann, N.; Elemento, O.; Viale, A.; Socci, N. D.; Abel, L.; Nagata, S.; Huse, M.; Miller, W. T.; Casanova, J. L.; Geissmann, F.
Article Title:	ACK1 and BRK non-receptor tyrosine kinase deficiencies are associated with familial systemic lupus and involved in efferocytosis
Abstract:	Systemic lupus erythematosus (SLE) is an autoimmune disease, the pathophysiology and genetic basis of which are incompletely understood. Using a forward genetic screen in multiplex families with SLE, we identified an association between SLE and compound heterozygous deleterious variants in the non-receptor tyrosine kinases (NRTKs) ACK1 and BRK. Experimental blockade of ACK1 or BRK increased circulating autoantibodies in vivo in mice and exacerbated glomerular IgG deposits in an SLE mouse model. Mechanistically, NRTKs regulate activation, migration, and proliferation of immune cells. We found that the patients' ACK1 and BRK variants impair efferocytosis, the MERTK-mediated anti-inflammatory response to apoptotic cells, in human induced pluripotent stem cell (hiPSC)-derived macrophages, which may contribute to SLE pathogenesis. Overall, our data suggest that ACK1 and BRK deficiencies are associated with human SLE and impair efferocytosis in macrophages. © 2024, Guillet, Lazarov et al.
Keywords:	adult; genetics; mouse; animal; metabolism; animals; mice; inflammation; protein tyrosine kinase; disease model; immunology; genomics; systemic lupus erythematosus; protein-tyrosine kinases; disease models, animal; macrophage; phagocytosis; macrophages; autoantibody; autoantibodies; lupus erythematosus, systemic; humans; human; male; female; efferocytosis; protein kinase mer; systemic lupus; genetic diseases; c-mer tyrosine kinase; ack1; brk
Journal Title:	eLife
Volume:	13
ISSN:	2050-084X
Publisher:	eLife Sciences Publications Ltd.
Date Published:	2024-11-21
Start Page:	RP96085
Language:	English
DOI:	10.7554/eLife.96085
PUBMED:	39570652
PROVIDER:	scopus
PMCID:	PMC11581429
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85210340337&doi=10.7554%2feLife.96085&partnerID=40&md5=c77119473000268bba5c2c9556dedb6b
Notes:	The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PubMed record and PDF. Corresponding MSK author is Tomi Lazarov -- Source: Scopus

https://synapse.mskcc.org/synapse/works/has_related_data_chk/221169