Rap1 signaling is required for suppression of Ras-generated reactive oxygen species and protection against oxidative stress in T lymphocytes.
Transient production of reactive oxygen species (ROS) plays an important role in optimizing transcriptional and proliferative responses to TCR signaling in T lymphocytes. Conversely, chronic oxidative stress leads to decreased proliferative responses and enhanced transcription of inflammatory gene products, and is thought to underlie the altered pathogenic behavior of T lymphocytes in some human diseases, such as rheumatoid arthritis (RA). Although the signaling mechanisms regulating ROS production in T lymphocytes has not been identified, activation of the small GTPase Ras has been shown to couple agonist stimulation to ROS production in other cell types. We find that Ras signaling via Ral stimulates ROS production in human T lymphocytes, and is required for TCR and phorbol ester-induced ROS production. The related small GTPase Rap1 suppresses agonist, Ras and Ral-dependent ROS production through a PI3K-dependent pathway, identifying a novel mechanism by which Rap1 can distally antagonize Ras signaling pathways. In synovial fluid T lymphocytes from RA patients we observed a high rate of endogenous ROS production, correlating with constitutive Ras activation and inhibition of Rap1 activation. Introduction of dominant-negative Ras into synovial fluid T cells restored redox balance, providing evidence that deregulated Ras and Rap1 signaling underlies oxidative stress and consequent altered T cell function observed in RA.
Remans
Philip H J
PH
Division of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Gringhuis
Sonja I
SI
van Laar
Jacob M
JM
Sanders
Marjolein E
ME
Papendrecht-van der Voort
Ellen A M
EA
Zwartkruis
Fried J T
FJ
Levarht
E W Nivine
EW
Rosas
Marcela
M
Coffer
Paul J
PJ
Breedveld
Ferdinand C
FC
Bos
Johannes L
JL
Tak
Paul P
PP
Verweij
Cornelis L
CL
Reedquist
Kris A
KA
D006801:Humans; D019169:Jurkat Cells; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013601:T-Lymphocytes / Q000378:metabolism*; D013997:Time Factors; D020827:rap1 GTP-Binding Proteins / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism*
D017382:Reactive Oxygen Species; D019869:Phosphatidylinositol 3-Kinases; D020928:Mitogen-Activated Protein Kinases; D020827:rap1 GTP-Binding Proteins; D018631:ras Proteins