• PNAS Alerting Services
  • Sign-up for PNAS eTOC Alerts

AP-4 mediates export of ATG9A from the trans-Golgi network to promote autophagosome formation

  1. Juan S. Bonifacinoa,2
  1. aCell Biology and Neurobiology Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892
  1. Edited by Pietro De Camilli, Howard Hughes Medical Institute and Yale University, New Haven, CT, and approved November 6, 2017 (received for review October 2, 2017)

Significance

A family of adaptor protein (AP) complexes functions to sort transmembrane cargos at different stages of the endomembrane system of eukaryotic cells. AP-4 is one of the most recently described and least well-understood members of this family. Interest in this complex has risen because mutations in any of its four subunits cause a form of hereditary spastic paraplegia (HSP) with intellectual disability. In this study, we demonstrate that AP-4 sorts ATG9A, the only transmembrane component of the core autophagy machinery, from the trans-Golgi network to peripheral compartments. This sorting is required to promote the early steps of autophagosome formation. Our observations implicate AP-4 as an autophagy regulator and altered autophagy as an underlying defect in AP-4–deficient HSP.

Abstract

AP-4 is a member of the heterotetrameric adaptor protein (AP) complex family involved in protein sorting in the endomembrane system of eukaryotic cells. Interest in AP-4 has recently risen with the discovery that mutations in any of its four subunits cause a form of hereditary spastic paraplegia (HSP) with intellectual disability. The critical sorting events mediated by AP-4 and the pathogenesis of AP-4 deficiency, however, remain poorly understood. Here we report the identification of ATG9A, the only multispanning membrane component of the core autophagy machinery, as a specific AP-4 cargo. AP-4 promotes signal-mediated export of ATG9A from the trans-Golgi network to the peripheral cytoplasm, contributing to lipidation of the autophagy protein LC3B and maturation of preautophagosomal structures. These findings implicate AP-4 as a regulator of autophagy and altered autophagy as a possible defect in AP-4–deficient HSP.

Footnotes

  • ?1R.M. and S.Y.P. contributed equally to this work.

  • ?2To whom correspondence should be addressed. Email: juan.bonifacino{at}nih.gov.
  • Author contributions: R.M., S.Y.P., and J.S.B. designed research; R.M., S.Y.P., R.D.P., and C.M.G. performed research; R.M., S.Y.P., and R.D.P. contributed new reagents/analytic tools; R.M., S.Y.P., R.D.P., C.M.G., and J.S.B. analyzed data; and R.M., S.Y.P., R.D.P., and J.S.B. wrote the paper.

  • The authors declare no conflict of interest.

  • This article is a PNAS Direct Submission.

  • This article contains supporting information online at www.danielhellerman.com/lookup/suppl/doi:10.1073/pnas.1717327114/-/DCSupplemental.

Published under the PNAS license.

Online Impact

                                      1. 99132880 2018-01-23
                                      2. 802899879 2018-01-23
                                      3. 295573878 2018-01-23
                                      4. 352668877 2018-01-23
                                      5. 984633876 2018-01-23
                                      6. 545928875 2018-01-23
                                      7. 976569874 2018-01-23
                                      8. 871324873 2018-01-23
                                      9. 263462872 2018-01-23
                                      10. 577161871 2018-01-23
                                      11. 255603870 2018-01-23
                                      12. 117346869 2018-01-23
                                      13. 90982868 2018-01-23
                                      14. 663415867 2018-01-23
                                      15. 793874866 2018-01-23
                                      16. 843582865 2018-01-23
                                      17. 864971864 2018-01-22
                                      18. 258841863 2018-01-22
                                      19. 957295862 2018-01-22
                                      20. 553518861 2018-01-22