PgmNr D135: A STRIPAK-like complex regulates axonal transport of autophagosomes and dense core vesicles by modulating PP2A activity.

Authors:
A. L. Neisch; T. P. Neufeld; T. S. Hays


Institutes
University of Minnesota, Minneapolis, MN.


Keyword: intracellular transport

Abstract:

Axonal transport is essential for neuronal function and survival, and dysregulation of this transport is associated with neurodegenerative disorders. Axonal transport is precisely regulated by adaptor and scaffolding protein complexes that mediate the linkage and transport of cargoes by kinesin and dynein motor proteins. In an RNAi screen for autophagosome transport defects we identified Connector of kinase to AP-1 (CKA), a scaffolding protein with a previously uncharacterized role in axonal transport. CKA is a regulatory subunit of the phosphatase PP2A and a scaffolding protein for the Striatin-interacting phosphatase and kinase (STRIPAK) complex. We find that CKA, together with the core STRIPAK components Mob4 and Strip, regulates retrograde axonal transport of autophagosomes and dense cores vesicles. Additionally we show that CKA is in a complex with dynein, suggesting that a STRIPAK-like complex may regulate dynein activity. Our results reveal that CKA also interacts directly with the autophagosomal membrane protein Atg8, potentially providing a linkage between dynein and its autophagosome cargo. Furthermore, we show that CKA’s ability to bind and regulate PP2A is required for dense core vesicle transport. Decreased PP2A activity is linked to neurodegenerative disease, and we find that dysregulation of PP2A activity by CKA disrupts axonal transport, which may contribute to disease progression. These findings demonstrate that a STRIPAK-like complex functions to regulate the transport of a subset of organelles important for both protein turnover and neuronal signaling, two processes essential for neuronal survival.



Flybase Genetic Index:
1. FlyBase gene symbol: Cka; FBgn: FBgn0044323
2. FlyBase gene symbol: Mob4; FBgn: FBgn0259483
3. FlyBase gene symbol: Strip; FBgn: FBgn0035437