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  • The Regulatory Subunit PPP2R2A of PP2A Enhances Th1 and Th17 Differentiation through Activation of the GEF-H1/RhoA/ROCK Signaling Pathway.

The Regulatory Subunit PPP2R2A of PP2A Enhances Th1 and Th17 Differentiation through Activation of the GEF-H1/RhoA/ROCK Signaling Pathway.

Journal of immunology (Baltimore, Md. : 1950) (2021-03-26)
Wenliang Pan, Kamalpreet Nagpal, Abel Suárez-Fueyo, Andrew Ferretti, Nobuya Yoshida, Maria G Tsokos, George C Tsokos
RÉSUMÉ

Protein phosphatase 2A (PP2A) composed of a scaffold subunit, a catalytic subunit, and multiple regulatory subunits is a ubiquitously expressed serine/threonine phosphatase. We have previously shown that the PP2A catalytic subunit is increased in T cells from patients with systemic lupus erythematosus and promotes IL-17 production by enhancing the activity of Rho-associated kinase (ROCK) in T cells. However, the molecular mechanism whereby PP2A regulates ROCK activity is unknown. In this study, we show that the PP2A regulatory subunit PPP2R2A is increased in T cells from people with systemic lupus erythematosus and binds to, dephosphorylates, and activates the guanine nucleotide exchange factor GEF-H1 at Ser885, which in turn increases the levels of RhoA-GTP and the activity of ROCK in T cells. Genetic PPP2R2A deficiency in murine T cells reduced Th1 and Th17, but not regulatory T cell differentiation and mice with T cell-specific PPP2R2A deficiency displayed less autoimmunity when immunized with myelin oligodendrocyte glycoprotein peptide. Our studies indicate that PPP2R2A is the regulatory subunit that dictates the PP2A-directed enhanced Th1 and Th17 differentiation, and therefore, it represents a therapeutic target for pathologies linked to Th1 and Th17 cell expansion.

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Anticorps monoclonal anti-β-actine antibody produced in mouse, clone AC-74, ascites fluid
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Anti-PP2A Antibody, C subunit, clone 1D6, clone 1D6, Upstate®, from mouse
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Rho-associated Kinase (ROCK) Activity Assay, This Rho-associated Protein Kinase (ROCK) Activity Assay Kit is an enzyme immunoassay for detection of the active ROCK & DMPK family kinases.
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Anti-phospho-Smad3 (Ser423/425) Antibody, from rabbit