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Dual function for Tango1 in secretion of bulky cargo and in ER-Golgi morphology

  1. M. Leptina,b,4
  1. aDirectors' Research Unit, European Molecular Biology Laboratory, 69117 Heidelberg, Germany;
  2. bInstitute of Genetics, University of Cologne, 50674 Cologne, Germany
  1. Edited by Kai Simons, Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany, and approved October 16, 2017 (received for review June 27, 2017)

Significance

Exporting bulky molecules poses challenges for cells, since the membrane vesicles that transport normal-sized molecules may not be sufficiently large. The protein Tango1 allows transport vesicles to grow much larger to accommodate bulky cargo. It has been puzzling why many smaller cargos also fail to be transported when Tango1 is absent. We show that this is because bulky cargos “clog up” the transport system, resulting in a general traffic jam. Once the blocking, large cargo is removed, the jam resulting from missing Tango1 is resolved, and other cellular stress signals also subside. However, structural defects in the transport system remain, showing that these are due to a direct requirement for Tango1, independent of its function in transport as such.

Abstract

Tango1 enables ER-to-Golgi trafficking of large proteins. We show here that loss of Tango1, in addition to disrupting protein secretion and ER/Golgi morphology, causes ER stress and defects in cell shape. We find that the previously observed dependence of smaller cargos on Tango1 is a secondary effect. If large cargos like Dumpy, which we identify as a Tango1 cargo, are removed from the cell, nonbulky proteins reenter the secretory pathway. Removal of blocking cargo also restores cell morphology and attenuates the ER-stress response. Thus, failures in the secretion of nonbulky proteins, ER stress, and defective cell morphology are secondary consequences of bulky cargo retention. By contrast, ER/Golgi defects in Tango1-depleted cells persist in the absence of bulky cargo, showing that they are due to a secretion-independent function of Tango1. Therefore, maintenance of ER/Golgi architecture and bulky cargo transport are the primary functions for Tango1.

Footnotes

  • ?1L.D.R.-B. and S.S. contributed equally to this work.

  • ?2Present address: Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Iceland, 101 Reykjavík, Iceland.

  • ?3Present address: Institute for Medical Information Processing, Biometry and Epidemiology, Ludwig-Maximilian University of Munich, 81377 Munich, Germany.

  • ?4To whom correspondence should be addressed. Email: mleptin{at}uni-koeln.de.
  • Author contributions: L.D.R.-B., S.S., M.B., and M.L. designed research; L.D.R.-B., S.S., and M.B. performed research; L.D.R.-B., S.S., and M.B. analyzed data; and L.D.R.-B., S.S., and M.L. 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.1711408114/-/DCSupplemental.

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