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ISGylation - a key to lock the cell gates for preventing the spread of threats.

Authors
  • Villarroya-Beltri, Carolina1, 2, 3
  • Guerra, Susana4
  • Sánchez-Madrid, Francisco5, 2, 3
  • 1 Vascular Pathophysiology Area, Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain. , (Spain)
  • 2 Immunology Service, Hospital de la Princesa, Universidad Autónoma de Madrid, 28006 Madrid, Spain. , (Spain)
  • 3 CIBER de Enfermedades Cardiovasculares, Instituto de Salud Carlos III, 28029 Madrid, Spain. , (Spain)
  • 4 Preventive Medicine Department, Facultad de Medicina, Universidad Autónoma de Madrid, 28029 Madrid, Spain. , (Spain)
  • 5 Vascular Pathophysiology Area, Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain [email protected] , (Spain)
Type
Published Article
Journal
Journal of Cell Science
Publisher
The Company of Biologists
Publication Date
Sep 15, 2017
Volume
130
Issue
18
Pages
2961–2969
Identifiers
DOI: 10.1242/jcs.205468
PMID: 28842471
Source
Medline
Keywords
License
Unknown

Abstract

Interferon stimulated gene 15 (ISG15) is an ubiquitin-like protein whose expression and conjugation to targets (ISGylation) is induced by infection, interferon (IFN)-α and -β, ischemia, DNA damage and aging. Attention has historically focused on the antiviral effects of ISGylation, which blocks the entry, replication or release of different intracellular pathogens. However, recently, new functions of ISGylation have emerged that implicate it in multiple cellular processes, such as DNA repair, autophagy, protein translation and exosome secretion. In this Review, we discuss the induction and conjugation of ISG15, as well as the functions of ISGylation in the prevention of infections and in cancer progression. We also offer a novel perspective with regard to the latest findings on this pathway, with special attention to the role of ISGylation in the inhibition of exosome secretion, which is mediated by fusion of multivesicular bodies with lysosomes. Finally, we propose that under conditions of stress or infection, ISGylation acts as a defense mechanism to inhibit normal protein translation by modifying protein kinase R (PKR, also known as EIF2AK2), while any newly synthesized proteins are being tagged and thus marked as potentially dangerous. Then, the endosomal system is re-directed towards protein degradation at the lysosome, to effectively 'lock' the cell gates and thus prevent the spread of pathogens, prions and deleterious aggregates through exosomes.

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