The ISG15 Conjugation System Broadly Targets Newly Synthesized Proteins: Implications for the Antiviral Function of ISG15

• Published in: Molecular cell 2010-06, Vol.38 (5), p.722-732
• Main Authors: Durfee, Larissa A., Lyon, Nancy, Seo, Kyungwoon, Huibregtse, Jon M.
• Format: Article
• Language: English
• Subjects: Antiviral Agents - metabolism; Capsid protein; Capsid Proteins - genetics; Capsid Proteins - metabolism; Cytokines - genetics; Cytokines - metabolism; Enzymes; HeLa Cells; Human papillomavirus; Human papillomavirus 16; Human papillomavirus 16 - pathogenicity; Humans; Infectivity; Interferon-beta - metabolism; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; MOLIMMUNO; Oncogene Proteins, Viral - genetics; Oncogene Proteins, Viral - metabolism; Polyribosomes; Polyribosomes - metabolism; Protein Biosynthesis - physiology; PROTEINS; RNA; Ubiquitins - genetics; Ubiquitins - metabolism
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2010.05.002

ISG15 is an interferon-induced and antiviral ubiquitin-like protein (Ubl). Herc5, the major E3 enzyme for ISG15, mediates the ISGylation of more than 300 proteins in interferon-stimulated cells. In addressing this broad substrate selectivity of Herc5, we found that: (1) the range of substrates extends even further and includes many exogenously expressed foreign proteins, (2) ISG15 conjugation is restricted to newly synthesized pools of proteins, and (3) Herc5 is physically associated with polyribosomes. These results lead to a model for ISGylation in which Herc5 broadly modifies newly synthesized proteins in a cotranslational manner. This further suggests that, in the context of an interferon-stimulated cell, newly translated viral proteins may be primary targets of ISG15. Consistent with this, we demonstrate that ISGylation of human papillomavirus (HPV) L1 capsid protein has a dominant-inhibitory effect on the infectivity of HPV16 pseudoviruses. [Display omitted] ► ISG15 is conjugated to an extremely broad range of cellular and foreign proteins ► Conjugation is limited to the newly synthesized pool of any given target protein ► Herc5, the ISG15 ligase, is associated with polysomes via the 60S ribosomal subunit ► In interferon-stimulated cells, new viral proteins may be primary targets of ISG15