SUMOylation of p53 mediates interferon activities

Abstract

There is growing evidence that many host proteins involved in innate and intrinsic immunity are regulated by SUMOylation, and that SUMO contributes to the regulatory process that governs the initiation of the type I interferon (IFN) response. The tumor suppressor p53 is a modulator of the IFN response that plays a role in virus-induced apoptosis and in IFN-induced senescence. Here we demonstrate that IFN treatment increases the levels of SUMOylated p53 and induces cellular senescence through a process that is partially dependent upon SUMOylation of p53. Similarly, we show that vesicular stomatitis virus (VSV) infection induces p53 SUMOylation, and that this modification favors the control of VSV replication. Thus, our study provides evidence that IFN signaling induces p53 SUMOylation, which results in the activation of a cellular senescence program and contributes to the antiviral functions of interferon.

KSHV latent protein LANA2 inhibits sumo2 modification of p53

“…12,14,15 Furthermore, SUMOylation of p53 is induced in response to DNA damage, interferon treatment, or viral infection, and SUMOylation has an important role in the induction of senescence by p53, 12,13,16,17 suggesting that this modification may represent a physiological response to activate p53 after virus infection. Thus, it is possible to speculate that inhibition of p53 SUMOylation may be a mechanism used by viral proteins to control p53 activity.…”

“…13 For this reason we evaluated senescence in H1299-p53 cells 13 transfected with LANA2-WT or the LANA2 mutants after treatment with 500 U/ml of b-interferon. As shown in Fig.…”

Interferon controls SUMO availability via the Lin28 and let-7 axis to impede virus replication

“…PML was also implicated in regulation of stem cell fate 51 , notably through TR2 sumoylation, which directly controls expression of Oct-4 (refs 52,53), or through p53 activation 54 . Thus, IFN-initiated, PML-enforced hypersumoylation may control stem cell self-renewal and/or proliferation 42,55 . Lin28 controls metabolism 19,56 , as recently shown for PML 57,58 .…”

“…40). Often in their sumoylated forms, some partners have been implicated in IFN effects on senescence (DAXX, p53, SP100) or antiviral defence (SP100) [41][42][43][44][45][46] . These unexpected findings therefore point to the existence of a highly integrated regulatory loop wherein the substrates, their modifiers (SUMOs) and the catalyser (PML NBs) are all dramatically upregulated during IFN response, promoting the rapid formation of the active, SUMO-conjugated form.…”

PML nuclear bodies: Assembly and oxidative stress-sensitive sumoylation

“…Critically, the sumoylated form of p53 was proposed to contribute to interferon effects on senescence. 131 In various settings, interferon-triggered cancer cell apoptosis or senescence involves PML and p53. [132][133][134][135][136] Similarly, both PML and sumoylation of DAXX were shown to be critical for interferon-triggered apoptosis in B cells.…”