T cell development involves TRAF3IP3-mediated ERK signaling in the Golgi
- J Exp Med. 2015 Jul 27;212(8):1323-36. doi: 10.1084/jem.20150110.
- 1. Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030.
- 2. Department of Genetics and Developmental Biology, University of Connecticut Health Center, Farmington, CT 06030.
- 3. Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030 The University of Texas Graduate School of Biomedical Sciences, Houston, TX 77030 [email protected].
Generation of T lymphocytes in the thymus is guided by signal transduction from the T cell receptor (TCR), but the underlying mechanism is incompletely understood. Here we have identified a Golgi-associated factor, TRAF3-interacting protein 3 (TRAF3IP3), as a crucial mediator of thymocyte development. TRAF3IP3 deficiency in mice attenuates the generation of mature thymocytes caused by impaired thymocyte-positive selection. TRAF3IP3 mediates TCR-stimulated activation of the mitogen-activated protein kinase (MAPK) extracellular signal-regulated kinase (ERK) and its upstream kinase mitogen/extracellular signal-regulated kinase (MEK). Interestingly, TRAF3IP3 exerts this signaling function through recruiting MEK to the Golgi and, thereby, facilitating the interaction of MEK with its activator BRAF. Transgenic expression of a constitutively active MEK rescues the T cell development block in Traf3ip3 knockout mice. These findings establish TRAF3IP3 as a novel regulator of T cell development and suggest a Golgi-specific ERK signaling mechanism that regulates thymocyte development.