Defects in ER–endosome contacts impact lysosome function in hereditary spastic paraplegia

Rachel Allison,Christian Beetz,Fiamma Berner,Jennifer Lippincott-Schwartz,James W Connell,Guy Pearson,Evan Reid,James R Edgar,Beate Winner,Tania Rizo,Timothy Newton,Sven Günther,Jürgen Winkler,Jennifer Hague

doi:10.1083/jcb.201609033

Abstract

Contacts between endosomes and the endoplasmic reticulum (ER) promote endosomal tubule fission, but the mechanisms involved and consequences of tubule fission failure are incompletely understood. We found that interaction between the microtubule-severing enzyme spastin and the ESCRT protein IST1 at ER-endosome contacts drives endosomal tubule fission. Failure of fission caused defective sorting of mannose 6-phosphate receptor, with consequently disrupted lysosomal enzyme trafficking and abnormal lysosomal morphology, including in mouse primary neurons and human stem cell-derived neurons. Consistent with a role for ER-mediated endosomal tubule fission in lysosome function, similar lysosomal abnormalities were seen in cellular models lacking the WASH complex component strumpellin or the ER morphogen REEP1. Mutations in spastin, strumpellin, or REEP1 cause hereditary spastic paraplegia (HSP), a disease characterized by axonal degeneration. Our results implicate failure of the ER-endosome contact process in axonopathy and suggest that coupling of ER-mediated endosomal tubule fission to lysosome function links different classes of HSP proteins, previously considered functionally distinct, into a unifying pathway for axonal degeneration.

Highlights

The endoplasmic reticulum (ER) consists of a series of sheets and dynamic tubules
We show that endosomal IST1 and an ER-localized isoform of spastin (M1-spastin) interact at ER–endosome contacts to promote endosomal tubule fission
Considered together, our experiments indicate that IST1 and M1-spastin interact at ER–endosome contact sites, and that this interaction is required for efficient ER-mediated fission of endosomal tubules

Summary

Introduction

The tubules make functionally important contacts with other organelles, including endosomes, mitochondria, and the plasma membrane (Raiborg et al, 2015). Contacts with endosomes are extensive, dynamic, and typically associated with microtubules (Friedman et al, 2013). They have been implicated in important cellular functions, including in fission of tubules from the endosomal body (Rowland et al, 2014). The molecular machinery underlying the establishment and breakage of these fission-related ER–endosome contact sites is not completely understood, the ER protein VAP has been implicated, via a mechanism that involves regulating endosomal phosphatidylinositol 4-phosphate levels and thereby the function of the WASH complex, an actin nucleating machinery that promotes endosomal tubule fission (Dong et al, 2016)

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Results

Conclusion