CHIP controls the expression of the neuropeptide precursor protein VGF

CHIP is a neuroprotective E3-ubiquitin ligase that supports longevity and healthy ageing. Loss of CHIP function has a major impact on life expectancy in animal models, whilst in humans’ mutations that compromise the E3-ligase activity of CHIP are causative for forms of Spinocerebellar Ataxia (SCA) that are accompanied by cognitive decline and/or dementia. The pathways regulated by CHIP to maintain neuronal health remain to be discovered. Gene-edited neuroblastoma cells were produced and used as a model to study the effects of CHIP loss on the steady state proteome in the absence of proteotoxic stress. Label free quantitative proteomic analysis (SWATH-MS) highlighted VGF, a member of the neuropeptide precursor family of proteins, as being a dominant protein responding to loss of CHIP function. By studying the dependence of VGF expression on CHIP using SILAC and RNA-Seq we have defined a role for the ligase in regulated neuropeptide expression.