Differential modulation of neurite growth by the S- and the L-forms of bag1, a co-chaperone of Hsp70

Abstract

Bag1 acts as a cochaperone for Hsp70. However, it also binds to members of the RAF family and to Akt. In addition, bag1 and Hsp70 are part of a complex with glucocorticoid receptors and thus modulate glucocorticoid receptor-mediated transcriptional activation. In the developing nervous system, bag1 is expressed in at least two isoforms. The L-form (bag1L) contains a nuclear localization signal and thus can translocate to the nucleus. In contrast, the S-form (bag1S) is localized exclusively in the cytoplasm. Former studies have shown that B-RAF is essential for neurotrophin-mediated survival signaling in motoneurons and sensory neurons, and that bag1 plays a role in coordinating B-RAF and Akt function in this context. In the absence of B-RAF, embryonic motoneurons and sensory neurons are not able to survive, indicating that bag1 and B-RAF are essential mediators for neuronal survival in response to neurotrophic factors during development. However, the role of the complex containing bag1, Hsp70 and B-RAF in mediating neurite growth in response to neurotrophic factors remained unclear. We have therefore studied the effect of bag1 overexpression in rat phaeochromocytoma (PC12) cells. Upon NGF treatment, proliferating PC12 become postmitotic and grow out neuronal processes. Bag1S overexpression interferes with neurite extension in PC12 cells. In contrast, bag1L does not disturb neurite outgrowth. Interaction of bag1S with Hsp70 appears necessary for this effect. These data indicate that the cytosolic form of bag1 participates in neurotrophin-mediated neurite growth, and that interaction with Hsp70 plays a crucial role in this context.