Cited by 39Autophagy in Disease and TherapyAmyotrophic Lateral Sclerosis ResearchCellular transport and secretion

WDR41 supports lysosomal response to changes in amino acid availability

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Amick, Joseph, Tharkeshwar, Arun Kumar, Amaya,, Catherine, Ferguson, Shawn M.·2018·Molecular Biology of the Cell

Abstract

C9orf72 mutations are a major cause of amyotrophic lateral sclerosis and frontotemporal dementia. The C9orf72 protein undergoes regulated recruitment to lysosomes and has been broadly implicated in control of lysosome homeostasis. However, although evidence strongly supports an important function for C9orf72 at lysosomes, little is known about the lysosome recruitment mechanism. In this study, we identify an essential role for WDR41, a prominent C9orf72 interacting protein, in C9orf72 lysosome recruitment. Analysis of human WDR41 knockout cells revealed that WDR41 is required for localization of the protein complex containing C9orf72 and SMCR8 to lysosomes. Such lysosome localization increases in response to amino acid starvation but is not dependent on either mTORC1 inhibition or autophagy induction. Furthermore, WDR41 itself exhibits a parallel pattern of regulated association with lysosomes. This WDR41-dependent recruitment of C9orf72 to lysosomes is critical for the ability of lysosomes to support mTORC1 signaling as constitutive targeting of C9orf72 to lysosomes relieves the requirement for WDR41 in mTORC1 activation. Collectively, this study reveals an essential role for WDR41 in supporting the regulated binding of C9orf72 to lysosomes and solidifies the requirement for a larger C9orf72 containing protein complex in coordinating lysosomal responses to changes in amino acid availability.

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  • C9orf72 forms a complex with SMCR8 and WDR41, which targets the complex to lysosomes and interacts with RB1CC1-ULK1-ATG13-ATG101 to regulate autophagosome formation.

    “C9orf72 also forms a complex with SMCR8, a guanine nucleotide exchange factor, and WDR41, a WD40 protein essential for targeting the C9orf72-SMCR8-WDR41 complex to lysosomes [146–150]. Here, this complex interacts with RB1CC1-ULK1-ATG13-ATG101, which together are involved in autophagosome formation [149].”

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Authors
Amick, J., Tharkeshwar, A. K., Amaya, & Ferguson, S. M.
Affiliations
Yale University (US)
Corresponding author
Ferguson, Shawn M.
Venue
Molecular Biology of the Cell
Published
2018-09
Volume
29
Issue
18
Pages
2213-2227
ISSN
  • 1059-1524 (ISSN-L)
  • 1939-4586
OpenAlex
W2815343175
Cited by
39
References
59
Citations by year
2026: 3 · 2025: 6 · 2024: 3 · 2023: 3 · 2022: 4 · 2021: 12 · 2020: 5 · 2019: 3
FWCI
3.90
Type
journal article
Language
en
Open access
Licence
cc-by-nc-sa
Locations
  • Molecular Biology of the Cell (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
Funders
  • Ellison Medical Foundation
  • National Institutes of Health
  • National Institute on Aging (P50AG047270)
  • National Institute of General Medical Sciences (T32GM007223, F31GM119249, R01GM105718)
Topics
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
Keywords
C9orf72, lysosomal homeostasis, amino acid starvation, mTORC1 signaling, SMCR8, amyotrophic lateral sclerosis, frontotemporal dementia, autophagy
MeSH terms
Autophagy-Related Proteins, C9orf72 Protein, Mechanistic Target of Rapamycin Complex 1, Amino Acids, Amyotrophic Lateral Sclerosis, Autophagy, Carrier Proteins, Humans, Lysosomes, Mutation, Signal Transduction, Frontotemporal Dementia

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