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

Abstract

Small ubiquitin-related modifier (SUMO) protein conjugation onto target proteins regulates multiple cellular functions, including defence against pathogens, stemness and senescence. SUMO1 peptides are limiting in quantity and are thus mainly conjugated to high-affinity targets. Conjugation of SUMO2/3 paralogues is primarily stress inducible and may initiate target degradation. Here we demonstrate that the expression of SUMO1/2/3 is dramatically enhanced by interferons through an miRNA-based mechanism involving the Lin28/let-7 axis, a master regulator of stemness. Normal haematopoietic progenitors indeed display much higher SUMO contents than their differentiated progeny. Critically, SUMOs contribute to the antiviral effects of interferons against HSV1 or HIV. Promyelocytic leukemia (PML) nuclear bodies are interferon-induced domains, which facilitate sumoylation of a subset of targets. Our findings thus identify an integrated interferon-responsive PML/SUMO pathway that impedes viral replication by enhancing SUMO conjugation and possibly also modifying the repertoire of targets. Interferon-enhanced post-translational modifications may be essential for senescence or stem cell self-renewal, and initiate SUMO-dependent proteolysis.

PML nuclear bodies: Assembly and oxidative stress-sensitive sumoylation

“…2). Interestingly, SUMO expression is also massively upregulated by interferons, through a recently elucidated microRNA based mechanism, 112 resulting in a global enrichment of SUMO conjugates. Although, unlike arsenicinduced sumoylation, interferon-enhanced sumoylation does not strictly depend on PML, PML does redistribute interferoninduced SUMO peptides toward NB partners.…”

“…Indeed, while PML enhances SP100 sumoylation upon exposure to interferon, sumoylation of RanGAP1 is favored in interferon-treated cells only when PML is absent. 26,112 This points to the existence of a highly coordinated interferon-responsive sumoylation network where PML NBs and SUMOs are induced altogether, greatly facilitating modifications (or degradation) of partner proteins (Fig. 2).…”

SUMOylation: A link to future therapeutics

“…This makes miR-146a and SERCA2a gene SUMOylation a combined target of therapies for heart failure patients (Oh, Lee et al, 2014). The enhanced production and conjugation of SUMO1/2/3 to target proteins after interferon induction through miRNA based mechanism involving Lin28 and let-7 axis helps impede virus replication (Sahin, Ferhi et al, 2014). It has been demonstrated that SUMOs improves antiviral ability of interferon's against HSV1 and HIV (Sahin, Ferhi et al, 2014).…”

“…The enhanced production and conjugation of SUMO1/2/3 to target proteins after interferon induction through miRNA based mechanism involving Lin28 and let-7 axis helps impede virus replication (Sahin, Ferhi et al, 2014). It has been demonstrated that SUMOs improves antiviral ability of interferon's against HSV1 and HIV (Sahin, Ferhi et al, 2014). This finding hence shows the integrated interferon responsive PML/SUMO pathway that reduces viral replication through SUMO conjugation and increased SUMO targets.…”

“…The discovery of PML/SUMO pathway that hinder viral replication by SUMO conjugation and might be increasing the number of SUMO targets, indicates a possible role in senescence or stem cell self renewal. (Sahin et al, 2014). Ubiquitination maintains the balance in cyclin-dependent kinase (CDK) activity by degradation of cyclins to maintain proper cell cycle progression.…”