Stress inhibits nucleocytoplasmic shuttling of heat shock protein hsc70

Abstract

Heat shock proteins of the hsp/hsc70 family are essential chaperones, implicated in the stress response, aging, and a growing number of human diseases. At the molecular level, hsc70s are required for the proper folding and intracellular targeting of polypeptides as well as the regulation of apoptosis. Cytoplasmic members of the hsp/hsc70 family are believed to shuttle between nuclei and cytoplasm; they are found in both compartments of unstressed cells. Our experiments demonstrate that actin filament-destabilizing drugs trigger the nuclear accumulation of hsc70s in unstressed and heat-shocked cells recovering from stress. Using human-mouse heterokaryons, we show that stress inhibits shuttling and sequesters the chaperone in nuclei. The inhibition of hsc70 shuttling upon heat shock is only transient, and transport is reestablished when cells recover from stress. Hsc70 shuttling is controlled by hsc70 retention in the nucleus, a process that is mediated by two distinct mechanisms, ATP-sensitive binding of hsc70s to chaperone substrates and, furthermore, the association with nucleoli. The nucleolar protein fibrillarin and ribosomal protein rpS6 were identified as components that show an increased association with hsc70s in the nucleus upon stress exposure. Together, our data suggest that stress abolishes the exit of hsc70s from the nucleus to the cytoplasm, thereby limiting their function to the nuclear compartment. We propose that during recovery from stress hsc70s are released from nuclear and nucleolar anchors, which is a prerequisite to restore shuttling.

P-glycoprotein traffics from the nucleus to the plasma membrane in rat brain endothelium during inflammatory pain

“…38 Hsc70 is a nucleocytoplasmic shuttle protein in other cell types in culture. 39,40 By identifying both the source and destination of the PgP in the endothelial cells, we can direct our efforts toward elucidating the steps in the PgP trafficking pathways that result in increased PgP at the PM after PIP.…”

Gold nanoparticles induce nuclear damage in breast cancer cells, which is further amplified by hyperthermia

“…A simplified model depicted in Fig. 10 integrates these observations; it proposes that unlike the transient perturbations caused by mild heat shock [53], the injuries produced by small gold nanospheres and gold nanoflowers are Fig. 8 Small gold nanospheres and gold nanoflowers reorganize the nucleolar subcompartments that synthesize RNA de novo.…”

“…The nucleolar accumulation of hsc70 is a well-established heat shock response that is likely linked to the proper organization and function of nucleoli [42,53,54]. When compared to vehicle or other GNPs, gold nanoflowers led to a small reduction of nucleolar hsc70 after heat shock (Fig.…”

“…GNPs combined with mild hyperthermia alter the subcellular distribution of hsc70, fibrillarin, and CAS A common feature shared by hsc70, fibrillarin, and CAS is their sensitivity to stress; all of the proteins relocate within the cell following an exposure to heat shock [42,45,52,53]. As their subcellular relocation and the biological activities of nucleoli can be measured in a quantitative fashion [42,45], these criteria were employed here to monitor the effect of GNPs.…”

Signaling pathways controlling activity-dependent local translation of BDNF and their localization in dendritic arbors

“…B5906; Dostie et al, 2000), goat antiribosomal protein S6 1:200 (Santa Cruz Biotechnology, cat. sc13007; Kodiha et al, 2005), rabbit anti-MAP2 1:200 (Santa Cruz Biotechnology, cat. sc20172), mouse anti-MAP2 1:200 (Sigma-Aldrich, cat.…”