Ramunas (Martin) Vabulas

Ramunas (Martin) Vabulas

ABSTRACT: HOW MAMMALIAN CELLS SENSE PROTEOSTASIS STRESS

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. We showed 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 competed 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).