Interferon Controls SUMO Availability via the Lin28 and let-7 Axis to Impede Virus Replication

Nat Commun. 2014 Jun 19;5:4187. doi: 10.1038/ncomms5187.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • HIV Infections / genetics
  • HIV Infections / immunology
  • HIV Infections / virology
  • HIV-1 / genetics
  • HIV-1 / physiology*
  • Herpes Simplex / genetics
  • Herpes Simplex / immunology
  • Herpes Simplex / virology
  • Herpesvirus 1, Human / genetics
  • Herpesvirus 1, Human / physiology*
  • Humans
  • Interferons / immunology
  • MicroRNAs / genetics
  • MicroRNAs / immunology*
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / immunology*
  • SUMO-1 Protein / genetics
  • SUMO-1 Protein / immunology*
  • Small Ubiquitin-Related Modifier Proteins / genetics
  • Small Ubiquitin-Related Modifier Proteins / immunology*
  • Ubiquitins / genetics
  • Ubiquitins / immunology*
  • Virus Replication

Substances

  • LIN28B protein, human
  • MicroRNAs
  • RNA-Binding Proteins
  • SUMO-1 Protein
  • SUMO2 protein, human
  • SUMO3 protein, human
  • Small Ubiquitin-Related Modifier Proteins
  • Ubiquitins
  • mirnlet7 microRNA, human
  • Interferons