DCAF1 controls T-cell function via p53-dependent and -independent mechanisms

Abstract

On activation, naive T cells grow in size and enter cell cycle to mount immune response. How the fundamental processes of T-cell growth and cell cycle entry are regulated is poorly understood. Here we report that DCAF1 (Ddb1–cullin4-associated-factor 1) is essential for these processes. The deletion of DCAF1 in T cells impairs their peripheral homeostasis. DCAF1 is upregulated on T-cell receptor activation and critical for activation-induced T-cell growth, cell cycle entry and proliferation. In addition, DCAF1 is required for T-cell expansion and function during anti-viral and autoimmune responses in vivo. DCAF1 deletion leads to a drastic stabilization of p53 protein, which can be attributed to a requirement of DCAF1 for MDM2-mediated p53 poly-ubiquitination. Importantly, p53 deletion rescues the cell cycle entry defect but not the growth defect of DCAF1-deficient cells. Therefore, DCAF1 is vital for T-cell function through p53-dependent and -independent mechanisms.

DCAF1 (VprBP): emerging physiological roles for a unique dual-service E3 ubiquitin ligase substrate receptor

“…However, regulation of p53 ubiquitylation remains incompletely understood and may involve other E3 ligases (Brooks and Gu, 2006). In keeping with this, Guo et al (2016) found that MDM2 overexpression increased p53 polyubiquitylation in U2OS cells, and that this effect was reversed by concomitant loss of DCAF1. However, the exact mechanism by which DCAF1 promotes ubiquitylation and degradation of p53 via MDM2 remains to be determined.…”

“…This study showed that DCAF1 depletion in U2OS cells increases expression of p53 and several of its target genes, including those encoding the cyclin-dependent kinase inhibitors p21 and p27. Consistent with this finding, conditional inactivation of Dcaf1 in T lymphocytes was found to stabilize p53 levels in DCAF1-deficient T cells and increase levels of p21 and the pro-apoptotic protein Bax (both products of p53 target genes) (Guo et al, 2016). p53 is known to be polyubiquitylated and degraded by the E3 ligase MDM2 (Haupt et al, 1997; Kubbutat et al, 1997).…”

“…Guo et al (2016) found that stimulation of T cell receptor (TCR) signaling in naïve CD4 + T cells elicits a transcription-independent increase in DCAF1 protein levels that is correlated with cell growth and proliferation, suggesting a role for DCAF1 in activated T cells. T cell-intrinsic inactivation of Dcaf1 in vivo at the double-positive stage of T cell development by Cd4Cre reduced numbers of both CD4 + and CD8 + T cells in spleen and peripheral lymph node, though T cell development in the thymus was not significantly perturbed (Guo et al, 2016). CD4 + T cells isolated from Dcaf1 fl / fl ; Cd4Cre mice failed to enter cell cycle and increase in size upon stimulation of TCR signaling.…”

“…CD4 + T cells isolated from Dcaf1 fl / fl ; Cd4Cre mice failed to enter cell cycle and increase in size upon stimulation of TCR signaling. The former defect was rescued by ablating p53 in DCAF1-deficient T cells, whereas as the defect in cell growth was not (Guo et al, 2016). The authors also demonstrated that loss of DCAF1 impaired T cell-mediated immunity in a model of lymphocytic choriomeningitis virus infection.…”

Promiscuous Targeting of Cellular Proteins by Vpr Drives Systems-Level Proteomic Remodeling in HIV-1 Infection

“…This is despite knockdown of DCAF1 in these cells, which reduces the DCAF1 protein abundance by approximately 50% (Figure S2B). In addition, at least 13 proteins co-immunoprecipitating with Vpr here have been reported previously to physically interact with DCAF1 alone (Coyaud et al., 2018, Guo et al., 2016, Hossain et al., 2017), of which 11 are not regulated by Vpr, and two, CEP78 and IQGAP2, are upregulated by Vpr, explaining their presence in this list of proteins.…”