A STR IPAK complex mediates axonal transport of autophagosomes and dense core vesicles through PP2A regulation

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Abstract

Autophagy plays an essential role in the cellular homeostasis of neurons, facilitating the clearance of cellular debris. This clearance process is orchestrated through the assembly, transport, and fusion of autophagosomes with lysosomes for degradation. The motor protein dynein drives autophagosome motility from distal sites of assembly to sites of lysosomal fusion. In this study, we identify the scaffold protein CKA (connector of kinase to AP-1) as essential for autophagosome transport in neurons. Together with other core components of the striatin-interacting phosphatase and kinase (STR IPAK) complex, we show that CKA associates with dynein and directly binds Atg8a, an autophagosomal protein. CKA is a regulatory subunit of PP2A, a component of the STR IPAK complex. We propose that the STR IPAK complex modulates dynein activity. Consistent with this hypothesis, we provide evidence that CKA facilitates axonal transport of dense core vesicles and autophagosomes in a PP2A-dependent fashion. In addition, CKA-deficient flies exhibit PP2A-dependent motor coordination defects. CKA function within the STR IPAK complex is crucial to prevent transport defects that may contribute to neurodegeneration.

Original languageEnglish (US)
Pages (from-to)441-461
Number of pages21
JournalJournal of Cell Biology
Volume216
Issue number2
DOIs
StatePublished - 2017

Bibliographical note

Funding Information:
We thank members of the Hays and Neufeld laboratories for helpful feedback on this work. We thank Annamarie Allen for technical assistance. We are grateful to Wei Du and Takahiro Chihara for providing antibodies, Steven Hou for providing the Cka2 allele and Cka clone, Yunyun Jin and Lei Zhang for providing the UAS-Flag-hpo and UASFlag-hpoT195E lines, and Richard Fehon for the GFP-yki construct. We thank Thomas Pengo for assistance with statistical analyses. We thank Sean Conner, Mary Porter, Adam Avery, Guillermo Marqu?s, Min-Gang Li, and Madeline Serr for critical reading of the manuscript. A portion of this work was done at the University of Minnesota University Imaging Centers. This work was funded by the American Heart Association postdoctoral grant 15POST22790015 to A.L. Neisch, the National Institutes of Health grant 2R01GM062509 to T.P. Neufeld, and the National Institutes of Health grant 5R01GM044757 to T.S. Hays.

Publisher Copyright:
© 2017 Neisch et al.

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