Commentary: BAG3 as a Mediator of Endosome Function and Tau Clearance

Abstract

Tauopathies are a group of heterogeneous neurodegenerative conditions characterized by the deposition of abnormal tau protein in the brain. The underlying mechanisms that contribute to the accumulation of tau in these neurodegenerative diseases are multifactorial; nonetheless, there is a growing awareness that dysfunction of endosome-lysosome pathways is a pivotal factor. BCL2 associated athanogene 3 (BAG3) is a multidomain protein that plays a key role in maintaining neuronal proteostasis. Further, recent data indicate that BAG3 plays an important role in mediating vacuolar-dependent degradation of tau. Overexpression of BAG3 in a tauopathy mouse model decreased pathological tau levels and alleviated synapse loss. High throughput screens of BAG3 interactors have identified key players in the vacuolar system; these include clathrin and regulators of small GTPases. These findings suggest that BAG3 is an important regulator of endocytic pathways. In this commentary, we discuss the potential mechanisms by which BAG3 regulates the vacuolar system and tau proteostasis.

Keywords: Arf6; BAG3; ESCRT; Rab35; TBC1D10B; tau.

Figure 1.. BAG3 interacts with clathrin, TBC1D10B and IQSEC3 to form a network regulating the endocytic pathway.

IQSEC3, a GEF, activates Arf6 promoting the GTP bounded state. Activated Arf6 recruits clathrin to the vacuolar membrane, and TBC1D10B is recruited to the clathrin-coated structures. TBC1D10B is a GAP that inactivates Rab35, and this process is controlled by BAG3. The activated Rab35 can inactivate Arf6 through ACAP2. The activated RAB35 will recruit the ESCRT-0 component, Hrs, which interacts with tau, and further recruit clathrin and other ESCRT machinery to endosome membrane. The recruitment of ESCRT machinery can ensure that the cargo, which is sequestered by ESCRT-0, will be efficiently sorted into forming one intraluminal vesicle (ILV). The recruited clathrin will dissociate from Hrs which allows it to proceed and promote the formation of the next ILV. During this process, BAG3 directly interacts with and sequestersTBC1D10B, attenuating its ability to inactivate Rab35. MVB, multivesicular body.