THE HUMAN CO-CHAPERONE HSP70-ESCORT PROTEIN 1 AS A NUCLEAR STRESS SENSOR

Human Hsp70-escort protein 1 (hHep1) is a co-chaperone that plays an important role to keep the mitochondrial Hsp70 (mtHsp70) soluble and functional. It is known that hHep1 is a mitochondrial matrix protein that stimulates the ATPase activity of mtHsp70 and is able to remodel Hsp70s supramolecular assemblies (SMAs) into smaller particles. Recently we reported that hHep1 is also found in nucleus, although its nuclear functions are unknown. Here, we observed that a fraction of hHep1 can translocate inside the nucleus and accumulate at nucleoli and PML nuclear bodies (PML-NBs) in response to proteotoxic stress. Recent evidence shows that these two condensates participate in the nuclear quality control and sequestering newly synthesized misfolded proteins, including defective ribosomal products (DRiPs). Upon stress, the fraction of hHep1 at PML-NBs also colocalizes with DRiPs in translation dependent-manner. Of note, the nuclear fraction of hHep1 increases over time during the stress recovery phase and silencing hHep1 delays the clearance of DRiPs from the nucleus, suggesting that hHep1 may be required to restore nuclear functionality. Besides HS, also treatments of mammalian cells with the proteasome inhibitor MG132 led to the nuclear translocation of a fraction of hHep1. In addition, for nuclear/cytoplasm fractionation we also performed a protocol to differentiate cytoplasmic proteins, nuclear soluble proteins and insoluble nuclear proteins. This fractionation showed that hHep1 increase in the nucleus was higher in the insoluble part, indicating that hHep1 may be interacting with chromatin. Our data suggest that, beyond its known mitochondrial functions, hHep1 may participate as a stress sensor from mitochondria to nucleus. Further studies will elucidate the exact function of hHep1 in the nucleus and will reveal whether hHep1 may participate in nuclear quality control.