CHIP as a membrane-shuttling proteostasis sensor

Elife. 2017 Nov 1:6:e29388. doi: 10.7554/eLife.29388.

Abstract

Cells respond to protein misfolding and aggregation in the cytosol by adjusting gene transcription and a number of post-transcriptional processes. In parallel to functional reactions, cellular structure changes as well; however, the mechanisms underlying the early adaptation of cellular compartments to cytosolic protein misfolding are less clear. Here we show that the mammalian ubiquitin ligase C-terminal Hsp70-interacting protein (CHIP), if freed from chaperones during acute stress, can dock on cellular membranes thus performing a proteostasis sensor function. We reconstituted this process in vitro and found that mainly phosphatidic acid and phosphatidylinositol-4-phosphate enhance association of chaperone-free CHIP with liposomes. HSP70 and membranes compete for mutually exclusive binding to the tetratricopeptide repeat domain of CHIP. At new cellular locations, access to compartment-specific substrates would enable CHIP to participate in the reorganization of the respective organelles, as exemplified by the fragmentation of the Golgi apparatus (effector function).

Keywords: cell biology; human; membrane; molecular chaperones; mouse; organelle; proteostasis; stress response; ubiquitin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Fibroblasts / metabolism
  • Humans
  • Membrane Proteins / metabolism*
  • Mice
  • Proteostasis*
  • Ubiquitin-Protein Ligases / metabolism*

Substances

  • Membrane Proteins
  • STUB1 protein, human
  • Ubiquitin-Protein Ligases