期刊
BLOOD
卷 133, 期 18, 页码 1977-1988出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2018-11-886028
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- National Institutes of Health Intramural Research Program, NIAID
- National Cancer Institute [HHSN261200800001E, P01 CA203657]
- NATIONAL CANCER INSTITUTE [ZIABC011633] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [ZIAAI000614, ZIAAI000646, ZIAAI000647, ZIAAI001175] Funding Source: NIH RePORTER
Ras-related C3 botulinum toxin substrate 2 (RAC2), through interactions with reduced NAD phosphate oxidase component p67(phox), activates neutrophil superoxide production, whereas interactions with p21-activated kinase are necessary for fMLF-induced actin remodeling. We identified 3 patients with de novo RAC2[E62K] mutations resulting in severe T-and B-cell lymphopenia, myeloid dysfunction, and recurrent respiratory infections. Neutrophils from RAC2[E62K] patients exhibited excessive superoxide production, impaired fMLF-directed chemotaxis, and abnormal macropinocytosis. Cell lines transfected with RAC2[E62K] displayed characteristics of active guanosine triphosphate (GTP)-bound RAC2 including enhanced superoxide production and increased membrane ruffling. Biochemical studies demonstrated that RAC2[E62K] retains intrinsic GTP hydrolysis; however, GTPase-activating protein failed to accelerate hydrolysis resulting in prolonged active GTPbound RAC2. Rac2(+/E62K) mice phenocopy the T-and B-cell lymphopenia, increased neutrophil F-actin, and excessive superoxide production seen in patients. This gain-of-function mutation highlights a specific, nonredundant role for RAC2 in hematopoietic cells that discriminates RAC2 from the related, ubiquitous RAC1.
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