The structure and global distribution of the endoplasmic reticulum network is actively regulated by lysosomes

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van Tartwijk, Francesca  ORCID logo
Lin, Julie Qiaojin 
Nijenhuis, Wilco 
Parutto, Pierre 

The endoplasmic reticulum (ER) comprises morphologically and functionally distinct domains, sheets and interconnected tubules. These domains undergo dynamic reshaping, in response to changes in the cellular environment. However, the mechanisms behind this rapid remodeling are largely unknown. Here, we report that ER remodeling is actively driven by lysosomes, following lysosome repositioning in response to changes in nutritional status: the anchorage of lysosomes to ER growth tips is critical for ER tubule elongation and connection. We validate this causal link via the chemo- and optogenetically driven re-positioning of lysosomes, which leads to both a redistribution of the ER tubules and its global morphology. Therefore, lysosomes sense metabolic change in the cell and regulate ER tubule distribution accordingly. Dysfunction in this mechanism during axonal extension may lead to axonal growth defects. Our results demonstrate a critical role of lysosome-regulated ER dynamics and reshaping in nutrient responses and neuronal development.

3101 Biochemistry and Cell Biology, 31 Biological Sciences
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Science advances
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American Association for the Advancement of Science
Wellcome Trust (203249/Z/16/Z)
Wellcome Trust (215943/Z/19/Z)
Engineering and Physical Sciences Research Council (EP/L015889/1)
Biotechnology and Biological Sciences Research Council (BB/H023917/1)
Medical Research Council (G0902243)
Medical Research Council (MR/K02292X/1)
EPSRC (1946113)
This research was funded by Infinitus (China) Company Ltd. (supporting M.L. and C.F.K.); a UKRI Engineering and Physical Sciences Research Council (EPSRC) grant (EP/L015889/1) awarded to the Centre for Doctoral Training in Sensor Technologies and Applications (supporting F.W.v.T.); a Sir Henry Wellcome Postdoctoral Fellowship from the Wellcome Trust (215943/Z/19/Z, to J.Q.L.); the Netherlands Organization for Scientific Research (NWO) (supporting W.N.); the European Research Council (ERC) (supporting L.K.); Wellcome Trust Collaborative Grant (203249/Z/16/Z to C.E.H. and C.F.K.); and the UK Dementia Research Institute, which receives its funding from UK DRI Ltd., funded by the UK Medical Research Council, Alzheimer’s Society, and Alzheimer’s Research UK (supporting E.A. and C.F.K.). D.H.’s research is supported by a PSL-Cambridge grant and an ERC grant, agreement no. 882673