Abstract
SummaryCHIP is an E3-ubiquitin ligase that contributes to healthy aging and has been characterized as neuroprotective. To elucidate dominant CHIP-dependent changes in protein steady-state levels in a patient-derived human neuronal model, CHIP function was ablated using gene-editing and an unbiased proteomic analysis conducted to compare knock-out and wild-type isogenic induced pluripotent stem cell (iPSC)-derived cortical neurons. Rather than a broad effect on protein homeostasis, loss of CHIP function impacted on a focused cohort of proteins from actin cytoskeleton signaling and membrane integrity networks. In support of the proteomics, CHIP knockout cells had enhanced sensitivity to induced membrane damage. We conclude that the major readout of CHIP function in cortical neurons derived from iPSC of a patient with elevate α-synuclein, Parkinson's disease and dementia, is the modulation of substrates involved in maintaining cellular “health”. Thus, regulation of the actin cytoskeletal and membrane integrity likely contributes to the neuroprotective function(s) of CHIP.
Highlights
C-terminus of HSC70 Interacting Protein (CHIP) is an E3-ubiquitin ligase originally identified by virtue of its ability to interact with HSC70 (Ballinger et al, 1999)
SUMMARY CHIP is an E3-ubiquitin ligase that contributes to healthy aging and has been characterized as neuroprotective
Rather than a broad effect on protein homeostasis, loss of CHIP function impacted on a focused cohort of proteins from actin cytoskeleton signaling and membrane integrity networks
Summary
C-terminus of HSC70 Interacting Protein (CHIP) is an E3-ubiquitin ligase originally identified by virtue of its ability to interact with HSC70 (Ballinger et al, 1999). The degree to which CHIP-mediated ubiquitination of unfolded and ‘‘damaged’’ heat shock protein (HSP)-client proteins contributes to the overall physiological function of this E3-ligase remains unclear. For example, in the form of hyperthermic conditions, loss of CHIP function leads to apoptosis at the cellular level and rapid death in mouse models (Dai et al, 2003). In response to hyperthermic conditions, heat shock transcription factor (HSF1)-containing chaperone complexes can be activated by CHIP-dependent mechanisms leading to increasing HSP70 levels (Dai et al, 2003). A recent study demonstrated some degree of cell-type variability in the response to loss of CHIP function. Whilst fibroblasts from patients with ataxia (SCAR16), expressing mutant CHIP, had an impaired heat shock response, the response in induced pluripotent stem cell (iPSC)-derived neurons from the same patients was relatively unaffected (Schuster et al, 2020)
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