Selective multifaceted E3 ubiquitin ligases barricade extreme defense: Potential therapeutic targets for neurodegeneration and ageing

The theme of “Balancing Acts of Selective Defenders: Emerging Multifaceted E3 Ubiquitin Ligases Determine Precision of Cellular fitness and Care” by Upadhyayet al., Aggregation of abnormal or damaged proteins into various cellular compartments is a major hallmark of neurodegeneration, protein conformational disorders and ageing. Increased understanding of cellular quality control system reveals how cells fight against this fatal aggregation immediately with a very strict multistep defense mechanism. In this figure, football ground represents the overall normal cellular and molecular mechanisms in brain as signified by green color grass on ground. Red color team represents various kinds of strikers and their attacks in the form of different cellular stresses such as oxidative stress, ER stress, genotoxic stress, proteasomal dysfunction, DNA damage and oncogene activation. Exposures of these cellular stresses generate misfolded or aggregated protein inclusions into various cellular compartments, represented here as a football. Under such cellular threats, cell responds in a variety of ways to defend itself against unwanted multifactorial toxic events in case of goal from stress team. Goal post denotes a cellular compartment where aggregation of misfolded proteins can be possible under the complete failure of QC system. Here, we depict cellular protein quality control (QC) system and few recently emerging crucial QC E3 ubiquitin ligases E6-AP (E6-Associated Protein), HRD1 (HMG-CoA Reductase Degradation 1 Homolog), ITCH (Itchy E3 Ubiquitin Protein) and MGRN1 (Mahogunin Ring Finger 1)respectively as goal keeper and associated defending team members, receiving cytoprotective survival help from molecular chaperones as denoted by the coach of the team. Illustration figured by Amit Mishra lab team.