SUMOylation: A link to future therapeutics

Abstract

SUMOylation, much of a similar process like ubiquitination catches attention across various research groups as a potential therapeutic target to fight various infectious and cancerous diseases. This idea take its strength from recent reports which unearth the molecular mechanisms of SUMOylation and its involvement in important diseases distributed across various kingdoms. At the beginning SUMOylation was considered a process affected only by viral diseases but subsequent reports enlighten its role in diseases caused by bacteria as well. This enhances the SUMOylation canvas and demanded more in-depth study of the process. The present review is an attempt to study the regulatory mechanism of genes when the natural SUMOylation pathway is disturbed, the cross-talk among SUMOylation and other post translational modifications, the role of miRNAs in controlling the function of transcripts, loading of RNA species into exosomes and the possible SUMOylation related therapeutic targets. IntroductionThe innate immune responses across kingdoms are tightly regulated to fight attacking pathogens. Post translational modification of proteins like acetylation, methylation, ubiquitination and SUMOylation have predominant role in activation/deactivation of immune responses by regulating various cellular processes including transcription, DNA repair, proliferation and apoptosis as these have the potential to relocate the protein to different organelles and modify its biological function. The deep understanding of those post translational mechanisms could provide insights in controlling several disease conditions and develop therapeutics based on those post translational modification markers.The small ubiquitin like modifiers (SUMO) proteins discovered in 1997 (Mahajan et al., 1997) has since been recognized as family of important modification proteins unlike ubiquitination which is involved in degradation of proteins, instead it modulates the function of target proteins. The covalent conjugation of SUMO molecules to protein residue lysine on a typical consensus sequence ψKxD/E (where ψ is large hydrophobic residue, K is the target lysine, D/E is acidic residue and x represent any amino acid) (Rodriguez et al., 2001;Sampson et al., 2001). The process of SUMOylation is carried out by a cascade of three enzymes (E1, E2 and E3). E1 is a SUMO activating enzyme SAE1, while E2 is conjugating enzyme e.g. Ubc9 and E3 is SUMO ligase. The SUMOylation reaction is reversed by SENPs termed as deSUMOylation having distinct regulatory roles. Till date four SUMO molecules have been reported in mammals viz., SUMO1, SUMO2, SUMO3 and SUMO4. The sequence similarity of SUMO2 and SUMO3 are almost 97% hence are often reported collectively as SUMO2/3. Various kinds of stimuli like oxidative stress often increase the rate of SUMOylation. A recent report shows the exposure to cigarette smoke alters the microRNA expression by SUMOylation of DICER (Gross et al., 2014). Viruses and chemical toxins also causes an increase in SUMOylation, a well known exam...

SUMO and SUMOylation Pathway at the Forefront of Host Immune Response

“…Both CD8 + cytotoxic T cells and CD4 + helper T cells differentiate into many different subtypes depending on the cytokine milieu in a context-dependent manner. The interplay between the innate and adaptive immune cells ultimately results in the efficient removal of the pathogens and the generation of the subsequent memory response (Beutler, 2004;Pascual et al, 2005;Hannoun et al, 2016;Khan et al, 2016;Adorisio et al, 2017).…”