Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 115, Issue 17, Pages E4051-E4060Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1801340115
Keywords
genome-wide CRISPR screen; TCR signaling; FAM49B; Rac1; actin cytoskeleton
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Funding
- National Basic Research Program of China [2015CB964601]
- National Natural Science Foundation of China [31670919]
- 1,000-Youth Elite Program of China
- NIH [R37AI114575]
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Despite decades of research, mechanisms controlling T cell activation remain only partially understood, which hampers T cell-based immune cancer therapies. Here, we performed a genome-wide CRISPR screen to search for genes that regulate T cell activation. Our screen confirmed many of the known regulators in proximal T cell receptor signaling and, importantly, also uncovered a previously uncharacterized regulator, FAM49B (family with sequence similarity 49 member B). FAM49B deficiency led to hyperactivation of Jurkat T cells following T cell receptor stimulation, as indicated by enhancement of CD69 induction, PAK phosphorylation, and actin assembly. FAM49B directly interacted with the active form of the small GTPase Rac, and genetic disruption of the FAM49BRac interaction compromised FAM49B function. Thus, FAM49B inhibits T cell activation by repressing Rac activity and modulating cytoskeleton reorganization.
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