Influenza B virus NS1 protein inhibits conjugation of the interferon (IFN)-induced ubiquitin-like ISG15 protein

Abstract

Of the several hundred proteins induced by interferon (IFN) a/b, the ubiquitin-like ISG15 protein is one of the most predominant. We demonstrate the novel way in which the function of the ISG15 protein is inhibited by in¯uenza B virus, which strongly induces the ISG15 protein: a speci®c region of the in¯uenza B virus NS1 protein, which includes part of its effector domain, blocks the covalent linkage of ISG15 to its target proteins both in vitro and in infected cells. We identify UBE1L as the E1 enzyme that catalyzes the ®rst activation step in the conjugation of ISG15, and show that the NS1B protein inhibits this activation step in vitro. In¯uenza A virus employs a different strategy: its NS1 protein does not bind the ISG15 protein, but little or no ISG15 protein is produced during infection. We discuss the likely basis for these different strategies.

Identification and characterization of two homologues of interferon-stimulated gene ISG15 in crucian carp

“…ISG15 is also the critical component in IFN-mediated inhibition of HIV-1 release [18]. Consistent with these findings, influenza A and B viruses have evolved different strategies to abolish the function of ISG15 in virus replication [19].…”

Serpin 2a Is Induced in Activated Macrophages and Conjugates to a Ubiquitin Homolog

“…It contains two ubiquitin-like domains with 43 and 62% homology to ubiquitin (10,14). The mechanism of conjugation of ISG15 to cellular substrates has been proposed to be analogous to that for ubiquitin involving homologous but not identical enzymes (22,23,43,44). Ubiquitin can form polyubiquitin chains from one lysine residue in a target protein, and it is possible that the spi2a-ISG15 complex with two ISG15 molecules is the result of a di-ISG15 chain.…”

“…ISG15 conjugation to spi2a may target spi2a to intermediate filaments allowing for regulation of protease activity at this site by this serpin. Interestingly, it has recently been shown that the influenza B virus NS1 protein inhibits conjugation of ISG15 to cellular proteins (44). This suggests that ISG15 conjugation is an effective part of the host response to viral infection, because pathogens often target pathways that decrease their ability to survive and replicate.…”

Expression, regulation and function of the ISGylation system in prostate cancer

“…Similar to ubiquitin, ISG15 is covalently conjugated to cytoplasmic and nuclear proteins, which function in diverse cellular pathways (Zhao et al, 2005). The coupling of ISG15 to its targets is a mechanism similar to the attachment of ubiquitin, and involves the ISG15-specific E1-like activating enzyme, Ube1L (Yuan and Krug, 2001), and the E2 enzyme, UbcH8, which also functions in ubiquitin conjugation (Kim et al, 2004;Zhao et al, 2004). Recently, two ubiquitin ligases, the estrogen-responsive finger protein (EFP) (Zou and Zhang, 2006) and Herc5 (Dastur et al, 2006), have been described to participate in ISG15 ligation.…”