CHIP as a membrane-shuttling proteostasis sensor

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).

CHIP-dependent regulation of the actin cytoskeleton is linked to neuronal cell membrane integrity

“…Likewise, previous proteomics identified ANXA5 (0.45-fold), HLA-B (0.22-fold) — as well as, FLNA (that here was below the level of detection by immunoblot but significantly changed in the MS analysis) — as putative CHIP substrates using an orthogonal substrate identification approach ( Bhuripanyo et al., 2018 ). Additionally, AHNAK (0.33-fold) is present in proteomics focused on the CHIP-interactome ( Kopp et al, 2017 ). (Note that all fold changes stated are derived from our proteomic screen).…”

“…The latter, however, only occurs in the absence of cellular stress ( Tawo et al., 2017 ). Also recently, it has been shown that CHIP can be transiently recruited to cellular membranes, having affinity for specific phospholipid species ( Kopp et al, 2017 ). CHIP localization to membranes is shown to be HSP70-independent, again pointing to a non-canonical function for CHIP in membrane protein regulation.…”

The E3 ubiquitin ligase CHIP in normal cell function and in disease conditions

“…SIRT6 K170 mediates the susceptibility to protein degradation in the absence of CHIP. These results suggest that another E3 ligase may be involved in SIRT6 ubiquitination . One of the potential mechanisms for CHIP regulation of the aging process may be through maintaining SIRT6 protein stability, allowing SIRT6 to participate in histone deacetylation and DNA repair activities.…”

“…CHIP‐K30A, which has a mutation in its chaperone‐binding domain, fails to recognize substrate proteins, suggesting that CHIP interacts with its substrates through the participation of chaperone protein . Although CHIP usually interacts with its substrates through a chaperone protein, it occasionally interacts with substrate proteins in a chaperone‐independent manner (Table ) …”

“…SIRT6 functions are involved in multiple molecular pathways related to aging, including DNA repair, telomere maintenance, glycolysis, and inflammation . CHIP stabilizes SIRT6 protein by preventing its proteasomal degradation . In Stub1 ‐KO cells, the half‐life of SIRT6 protein is substantially reduced due to increased proteasomal degradation.…”