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

Abstract

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.

Protocadherin-7 Regulates Osteoclast Differentiation through Intracellular SET-Binding Domain-Mediated RhoA and Rac1 Activation

“…A study has reported that Pcdh7 recruits SET along with protein phosphatase 2A (PP2A), which is inhibited by SET, thereby suppressing PP2A activity [ 14 ]. PP2A has been shown to regulate RhoA in T cells [ 41 ], and Rac1 in lung cancer [ 42 ], implying SET-mediated regulation of PP2A in osteoclasts. Future studies will be required to understand the molecular function of SET in Pcdh7-mediated regulation of osteoclast differentiation.…”

ROCK Inhibition as Potential Target for Treatment of Pulmonary Hypertension

“…In contrast, regulatory T cells (T reg ) are implicated in suppressing immune responses on the vessel wall indicating anti-inflammatory role in PH [ 43 , 109 , 165 ]. In addition to the mediation of lymphocyte chemotaxis, ROCK activity also regulates T cell activation, proliferation and cytokine production [ 27 , 121 , 166 , 167 , 168 ]. Isoform-selective responses are suggested, because ROCK1 and ROCK2 modulate the polarization of CD4 T cells to T h 2 and T h 1/T h 17 phenotypes, respectively [ 27 , 113 , 167 , 169 ].…”

“…In addition to the mediation of lymphocyte chemotaxis, ROCK activity also regulates T cell activation, proliferation and cytokine production [ 27 , 121 , 166 , 167 , 168 ]. Isoform-selective responses are suggested, because ROCK1 and ROCK2 modulate the polarization of CD4 T cells to T h 2 and T h 1/T h 17 phenotypes, respectively [ 27 , 113 , 167 , 169 ]. ROCK2 inhibition reduces the phosphorylation of STAT-1 and STAT-3 and increases phosphorylated STAT-5, thus favoring T reg polarization instead of T h 1/T h 17 and locally controlling immune cell activation [ 126 , 170 ].…”

PP2A and Its Inhibitors in Helper T-Cell Differentiation and Autoimmunity

“…PP2A also contributes to CD4+ T-cell differentiation. Genetic deletion of a PP2A regulatory subunit PPP2R2A in mice led to reduction in Th1 differentiation in vitro as measured by IFNγ expression ( 65 ). Interestingly, PP2A inhibition by a small molecule PP2A inhibitor LB100 led to increase in Th1 differentiation in mice ( 66 ).…”