A Critical Role for ISGylation, Ubiquitination and, SUMOylation in Brain Damage: Implications for Neuroprotection

Post-translational modification (PTMs) of proteins by ubiquitin and ubiquitin-like modifiers such as interferon-stimulated gene 15 (ISG15) and small ubiquitin-related modifier (SUMO) play a critical role in the regulation of brain pathophysiology. Protein ISGylation is a covalent attachment of ISG15 to its target proteins, which is a unique PTM among other ubiquitin-like modifiers. Although, ISG15 shares sequence homology to ubiquitin, yet the functional significance of protein ISGylation is distinct from ubiquitination and SUMOylation. Further, ISG15 highly conserved among vertebrate species, unlike the other ubiquitin-like modifiers. ISGylation modulates various intracellular mechanisms such as Janus kinase/signal transducers and activators of transcription (JAK-STAT) pathway, autophagy, DNA repair, etc., indicating its biological significance. ISGylation emerged as one of the important mechanisms in the regulation of various neurological disorders including stroke, traumatic brain injury (TBI), basal ganglia calcification, and ataxia-telangiectasia. It appears that protein ISGylation is an endogenous neuroprotective mechanism. This review discusses the role of ISGylation in various brain pathologies with a particular emphasis on cerebral ischemia/stroke and on structural similarities between ISG15 and ubiquitin. Further, recent advancements on the role of ubiquitination and SUMOylation with relevance to ISGylation will also be discussed. The overall goal is to provide better insights on the mechanistic link between ISGylation and other ubiquitin-like modifiers, which may be helpful to establish novel therapeutic strategies for neuroprotection.