WDR41 supports lysosomal response to changes in amino acid availability
Open accessAbstract
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].”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [147]
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Lukmani, F., Shillingford, J. M., Brauer, M., Pancholi, D., St‐Germain, J. R., Shayman, J. A., Raught, B., & Gupta, G. D. (2025) · Molecular & Cellular Proteomics · doi:10.1016/j.mcpro.2025.101091 · Cited by 3 · see citing works
LRP10 promotes trafficking of progranulin and prosaposin to lysosomesPreprint
Filippini, F., Devireddy, S., & Ferguson, S. M. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.05.02.651888 · Cited by 2 · see citing works
Self-citationStructural basis for the ARF GAP activity and specificity of the C9orf72 complexPreprint
Su, M.-Y., Fromm, S. A., Remis, J. P., Toso, D. B., & Hurley, J. H. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.04.13.439632
Identifying novel, conditional and joint genetic effects on Parkinson's disease risk
Rodrigo, U. L. M. (2021) · Queensland University of Technology · doi:10.5204/thesis.eprints.212754
Sharma, N., Revanasiddu, D., Kumar, S., Sinha, B., KUMARI, R., GUPTA, I. D., & Verma, A. (2022) · The Indian Journal of Animal Sciences · doi:10.56093/ijans.v92i2.122096
JIP4 deficiency causes a lysosomal storage disease arising from impaired cystine effluxPreprint
Nassar, L. M., Shi, X., Roczniak-Ferguson, A., Shen, H., & Ferguson, S. M. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.06.06.657909
Self-citationRNA interactions drive structural and functional diversification of α-Synuclein fibrilsPreprint
Rupert, J., Palma, F. D., Colantoni, A., Intze, A., Temperini, M. E., Giliberti, V., Zacco, E., & Tartaglia, G. G. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.11.30.691421
Structural and functional characterization of the lysosomal amino acid transporter PQLC2
Jamal, L. (2024) · theses.fr (ABES) · doi:10.70675/657f2ba1z9911z43bbza9c9zd6f6ab1aba13
Wang, J., Davis, C. T., Kunzelmann, S., Maslen, S., Kelly, G., Skehel, M. J., & Schreiber, A. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.04.16.718395
RNA interactions drive structural and functional diversification of α-Synuclein fibrilsPreprint
Tartaglia, G. G., Rupert, J., Palma, F. D., Colantoni, A., Intze, A., Temperini, M. E., Giliberti, V., & Zacco, E. (2026) · Research Square · doi:10.21203/rs.3.rs-9032720/v1
Sex-biased Genetic Risk Loci and Causal Brain Proteins in Parkinson’s DiseasePreprint
Cook, N., Zeng, Y., Fu, T., Yang, C., Sivasankaran, S. K., Nguyen, P., FinnGen, Wingo, A. P., Wingo, T. S., Foo, J. N., et al. (2026) · medRxiv · doi:10.64898/2026.06.23.26356345
- 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
- PMC
- PMC6249801
- 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
- green
- www.ncbi.nlm.nih.gov
- 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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