title: A Decade of Boon or Burden: What Has the CHIP Ever Done for Cellular Protein Quality Control Mechanism Implicated in Neurodegeneration and Aging?
abstract: Cells regularly synthesize new proteins to replace old and abnormal proteins for normal cellular functions. Two significant protein quality control pathways inside the cellularmilieuare ubiquitin proteasome system (UPS) and autophagy. Autophagy is known for bulk clearance of cytoplasmic aggregated proteins, whereas the specificity of protein degradation by UPS comes from E3 ubiquitin ligases. Few E3 ubiquitin ligases, like C-terminus of Hsc70-interacting protein (CHIP) not only take part in protein quality control pathways, but also plays a key regulatory role in other cellular processes like signaling, development, DNA damage repair, immunity and aging. CHIP targets misfolded proteins for their degradation through proteasome, as well as autophagy; simultaneously, with the help of chaperones, it also regulates folding attempts for misfolded proteins. The broad range of CHIP substrates and their associations with multiple pathologies make it a key molecule to work upon and focus for future therapeutic interventions. E3 ubiquitin ligase CHIP interacts and degrades many protein inclusions formed in neurodegenerative diseases. The presence of CHIP at various nodes of cellular protein-protein interaction network presents this molecule as a potential candidate for further research. In this review, we have explored a wide range of functionality of CHIP inside cells by a detailed presentation of its co-chaperone, E3 and E4 enzyme like functions, with central focus on its protein quality control roles in neurodegenerative diseases. We have also raised many unexplored but expected fundamental questions regarding CHIP functions, which generate hopes for its future applications in research, as well as drug discovery.
authors.affiliation: Cellular and Molecular Neurobiology Unit, Indian Institute of Technology Jodhpur Rajasthan, India.
authors.forename: Vibhuti
authors.initials: V
authors.lastname: Joshi
authors.affiliation: Cellular and Molecular Neurobiology Unit, Indian Institute of Technology Jodhpur Rajasthan, India.
authors.forename: Ayeman
authors.initials: A
authors.lastname: Amanullah
authors.affiliation: Cellular and Molecular Neurobiology Unit, Indian Institute of Technology Jodhpur Rajasthan, India.
authors.forename: Arun
authors.initials: A
authors.lastname: Upadhyay
authors.affiliation: Cellular and Molecular Neurobiology Unit, Indian Institute of Technology Jodhpur Rajasthan, India.
authors.forename: Ribhav
authors.initials: R
authors.lastname: Mishra
authors.affiliation: Centre for Biosciences and Biomedical Engineering, Indian Institute of Technology Indore Madhya Pradesh, India.
authors.forename: Amit
authors.initials: A
authors.lastname: Kumar
authors.affiliation: Cellular and Molecular Neurobiology Unit, Indian Institute of Technology Jodhpur Rajasthan, India.
authors.forename: Amit
authors.initials: A
authors.lastname: Mishra
keywords: E3 ubiquitin ligases; aging; cell death; misfolded proteins; neurodegeneration