Fighting mycobacteria through ISGylation.

Our bodies use interferon (IFN) signalling as a central pathway to limit the spread of pathogens, such as viruses, bacteria and parasites. After pathogen exposure, IFN production leads to the activation of immune cells—such as natural killer cells, macrophages and T lymphocytes—which mediate pathogen clearance. There are two main types of IFN signalling, type I and II. In type I signalling, IFNs α and β—produced mainly by leukocytes and fibroblasts, respectively—stimulate macrophages and natural killer (NK) cells to initiate an antiviral response. In type II signalling, IFNγ from activated T cells and NK cells potentiate type I signalling and promote inflammation. During type I signalling IFNα and IFNβ bind to their cognate receptors, which results in the induction of IFN-stimulated genes (ISGs). A key function of ISGs is to interfere with viral replication, hence the name interferon. One of the most strongly induced ISGs is ISG15, a small protein consisting of two ubiquitin folds connected with a hinge spacer, thus resembling di-ubiquitin [1]. It has been proposed that ISGylation is antiviral in mice, but its effects on human virus infection or other functional roles have been a long-standing question in the field. A study by the Casanova group provides important new insights into the role of ISG15 in humans, showing it is essential in the defence against mycobacterial disease but dispensable for other types of infection [2]. Similarly to ubiquitin, ISG15 can be conjugated to other proteins and several hundred targets have been suggested from proteomic studies [3]. However, few targets have been carefully evaluated, among them JAK1, STAT1, ERK1/2, PLCγ1, p63, PML-RARα, UBC13, filamin B and several viral proteins. In analogy to the ubiquitin system, ISG15 conjugation is mediated by an enzymatic cascade consisting of an E1 activating enzyme Ube1L, an E2 conjugating enzyme UbcH8 and a HECT-domain containing E3 ligase HERC5 (Fig 1A). Notably, both ISG15 and the E1/E2/E3 cascade are induced by type I IFN signalling. Knowledge of the biological functions of ISGylation comes mainly from the analysis of knockout mice for ISG15, Ube1L and from in vitro studies. ISG15–/– mice are more prone to infection by certain viruses, such as Sindbis, influenza A/B and herpes simplex 1 [4]. Ube1L–/– mice are also sensitized towards Sindbis and influenza infections [5]. Furthermore, ISG15 can inhibit the budding of certain viruses and modify viral proteins, and some viruses have developed strategies to inhibit ISGylation, underscoring the function of ISG15 and ISGylation in the antiviral response [6]. However, other viruses—such as vesicular stomatitis and lymphocytic choriomeningitis virus—have similar effects on ISG15–/– and wild-type mice [7], suggesting specialized functions of ISGylation after viral infection. In addition, Fighting mycobacteria through ISGylation