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Loss of Grp170 results in catastrophic disruption of endoplasmic reticulum function. | LitMetric

AI Article Synopsis

  • GRP170 is essential for mouse embryonic development and its absence in kidney nephrons causes renal failure; it's the only chaperone in the ER lumen.
  • Research involved creating mouse embryonic fibroblasts with engineered LoxP sites and a doxycycline-regulated Cre recombinase, leading to GRP170 depletion and cell death.
  • As GRP170 levels decreased, BiP's function was disrupted, resulting in increased binding to aggregation-prone proteins, triggering the unfolded protein response (UPR), and offering insights into the link between GRP170 mutations and human diseases.

Article Abstract

GRP170 () is required for mouse embryonic development, and its ablation in kidney nephrons leads to renal failure. Unlike most chaperones, GRP170 is the lone member of its chaperone family in the ER lumen. However, the cellular requirement for GRP170, which both binds nonnative proteins and acts as nucleotide exchange factor for BiP, is poorly understood. Here, we report on the isolation of mouse embryonic fibroblasts obtained from mice in which LoxP sites were engineered in the loci (). A doxycycline-regulated Cre recombinase was stably introduced into these cells. Induction of Cre resulted in depletion of Grp170 protein which culminated in cell death. As Grp170 levels fell we observed a portion of BiP fractionating with insoluble material, increased binding of BiP to a client with a concomitant reduction in its turnover, and reduced solubility of an aggregation-prone BiP substrate. Consistent with disrupted BiP functions, we observed reactivation of BiP and induction of the unfolded protein response (UPR) in futile attempts to provide compensatory increases in ER chaperones and folding enzymes. Together, these results provide insights into the cellular consequences of controlled Grp170 loss and provide hypotheses as to why mutations in the locus are linked to human disease.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11064666PMC
http://dx.doi.org/10.1091/mbc.E24-01-0012DOI Listing

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