Structure of the HOPS tethering complex, a lysosomal membrane fusion machinery
- Osnabrück University, Germany
- Philipp University of Marburg, Germany
- University of Münster, Germany
Abstract
Lysosomes are essential for cellular recycling, nutrient signaling, autophagy, and pathogenic bacteria and viruses invasion. Lysosomal fusion is fundamental to cell survival and requires HOPS, a conserved heterohexameric tethering complex. On the membranes to be fused, HOPS binds small membrane-associated GTPases and assembles SNAREs for fusion, but how the complex fulfills its function remained speculative. Here, we used cryo-electron microscopy to reveal the structure of HOPS. Unlike previously reported, significant flexibility of HOPS is confined to its extremities, where GTPase binding occurs. The SNARE-binding module is firmly attached to the core, therefore, ideally positioned between the membranes to catalyze fusion. Our data suggest a model for how HOPS fulfills its dual functionality of tethering and fusion and indicate why it is an essential part of the membrane fusion machinery.
Data availability
All diffraction data are deposited in the PDB as indicated in the manuscript. PDB files are mentioned there.
Article and author information
Author details
Christian Ungermann
Funding
Deutsche Forschungsgemeinschaft (SFB 944,P11)
- Christian Ungermann
Deutsche Forschungsgemeinschaft (SFB 944,P27)
- Arne Moeller
Deutsche Forschungsgemeinschaft (SFB 944,P20)
- Florian Fröhlich
Deutsche Forschungsgemeinschaft (UN111/5-6)
- Arne Moeller
- Christian Ungermann
Deutsche Forschungsgemeinschaft (INST190/196-1 FUGG)
- Arne Moeller
Bundesministerium fur Bildung und Forschung (BMBF/DLR 01ED2010)
- Arne Moeller
Deutsche Forschungsgemeinschaft (SFB 944,P16)
- Daniel Kümmel
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2022, Shvarev et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Structure of the HOPS tethering complex, a lysosomal membrane fusion machinery
eLife 11:e80901.
https://doi.org/10.7554/eLife.80901
Further reading
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- Cell Biology
Niemann–Pick disease type C (NPC) is a devastating lysosomal storage disease characterized by abnormal cholesterol accumulation in lysosomes. Currently, there is no treatment for NPC. Transcription factor EB (TFEB), a member of the microphthalmia transcription factors (MiTF), has emerged as a master regulator of lysosomal function and promoted the clearance of substrates stored in cells. However, it is not known whether TFEB plays a role in cholesterol clearance in NPC disease. Here, we show that transgenic overexpression of TFEB, but not TFE3 (another member of MiTF family) facilitates cholesterol clearance in various NPC1 cell models. Pharmacological activation of TFEB by sulforaphane (SFN), a previously identified natural small-molecule TFEB agonist by us, can dramatically ameliorate cholesterol accumulation in human and mouse NPC1 cell models. In NPC1 cells, SFN induces TFEB nuclear translocation via a ROS-Ca2+-calcineurin-dependent but MTOR-independent pathway and upregulates the expression of TFEB-downstream genes, promoting lysosomal exocytosis and biogenesis. While genetic inhibition of TFEB abolishes the cholesterol clearance and exocytosis effect by SFN. In the NPC1 mouse model, SFN dephosphorylates/activates TFEB in the brain and exhibits potent efficacy of rescuing the loss of Purkinje cells and body weight. Hence, pharmacological upregulating lysosome machinery via targeting TFEB represents a promising approach to treat NPC and related lysosomal storage diseases, and provides the possibility of TFEB agonists, that is, SFN as potential NPC therapeutic candidates.
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