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RNA Granules Hitchhike on Lysosomes for Long-Distance Transport, Using Annexin A11 as a Molecular Tether

69 Pages Posted: 11 Jan 2019 Sneak Peek Status: Under Review

See all articles by Ya-Cheng Liao

Ya-Cheng Liao

Howard Hughes Medical Institute (HHMI) - Chevy Chase - Janelia Research Campus

Michael Fernandopulle

National Institutes of Health (NIH) - National Institute of Neurological Disorders and Stroke (NINDS)

Guozhen Wang

University of Cambridge - Cambridge Institute for Medical Research

Heejun Choi

Howard Hughes Medical Institute (HHMI) - Chevy Chase - Janelia Research Campus

Ling Hao

National Institutes of Health (NIH) - National Institute of Neurological Disorders and Stroke (NINDS)

Catherine M. Drerup

Government of the United States of America - National Institute of Child Health and Human Development (NICHD)

Seema Qamar

University of Cambridge - Cambridge Institute for Medical Research

Jonathon Nixon-Abell

University of Cambridge - Cambridge Institute for Medical Research

Yi Shen

University of Cambridge - Department of Chemistry

William Meadows

University of Cambridge - Cambridge Institute for Medical Research

Michele Vendruscolo

University of Cambridge - Department of Chemistry

Tuomas Knowles

University of Cambridge - Department of Chemistry

Matthew Nelson

National Institutes of Health (NIH) - National Institute of Neurological Disorders and Stroke (NINDS)

Magda Czekalska

University of Cambridge - Cambridge Institute for Medical Research

Greta Musteikyte

University of Cambridge - Cambridge Institute for Medical Research

Rajan Patel

National Institutes of Health (NIH) - National Institute of Neurological Disorders and Stroke (NINDS)

Christina Stephens

National Institutes of Health (NIH) - National Institute of Neurological Disorders and Stroke (NINDS)

Amalia Pasolli

Howard Hughes Medical Institute (HHMI) - Chevy Chase - Janelia Research Campus

Lucy Forrest

National Institutes of Health (NIH) - National Institute of Neurological Disorders and Stroke (NINDS)

Peter St George-Hyslop

University of Cambridge - Cambridge Institute for Medical Research

Jennifer Lippincott-Schwartz

Howard Hughes Medical Institute (HHMI) - Chevy Chase - Janelia Research Campus

Michael E. Ward

National Institutes of Health (NIH) - National Institute of Neurological Disorders and Stroke (NINDS)

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Abstract

Long-distance RNA transport plays a critical role in cells by enabling local protein translation at metabolically-active sites distant from the nucleus. This ensures an appropriate spatial organization of proteins, vital to polarized cells such as neurons. Here, we present a novel mechanism for RNA transport, in which RNA granules indirectly “hitchhike” on moving lysosomes. In vitro biophysical modeling, live-cell microscopy, and unbiased proteomics reveal that annexin A11 (ANXA11), an RNA granule-associated phosphoinositide-binding protein, acts as an adaptor between RNA granules and lysosomes. ANXA11 possesses an Nterminal low complexity domain, facilitating its phase separation into membraneless RNA granules, and a C-terminal membrane binding domain, enabling interactions with lysosomes. ALS-associated mutations in ANXA11 decrease long-range transport of RNA granules in neurons by disrupting their docking onto lysosomes. Thus, ANXA11 enables neuronal RNA transport via lysosomal hitchhiking of RNA granules, performing a critical cellular function that is disrupted in ALS.

Suggested Citation

Liao, Ya-Cheng and Fernandopulle, Michael and Wang, Guozhen and Choi, Heejun and Hao, Ling and Drerup, Catherine M. and Qamar, Seema and Nixon-Abell, Jonathon and Shen, Yi and Meadows, William and Vendruscolo, Michele and Knowles, Tuomas and Nelson, Matthew and Czekalska, Magda and Musteikyte, Greta and Patel, Rajan and Stephens, Christina and Pasolli, Amalia and Forrest, Lucy and George-Hyslop, Peter St and Lippincott-Schwartz, Jennifer and Ward, Michael E., RNA Granules Hitchhike on Lysosomes for Long-Distance Transport, Using Annexin A11 as a Molecular Tether (January 9, 2019). Available at SSRN: https://ssrn.com/abstract=3312723 or http://dx.doi.org/10.2139/ssrn.3312723
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Ya-Cheng Liao (Contact Author)

Howard Hughes Medical Institute (HHMI) - Chevy Chase - Janelia Research Campus

19700 Helix Drive
Ashburn, VA 20147
United States

Michael Fernandopulle

National Institutes of Health (NIH) - National Institute of Neurological Disorders and Stroke (NINDS)

9000 Rockville Pike
Bethesda, MD 20892
United States

Guozhen Wang

University of Cambridge - Cambridge Institute for Medical Research

Trinity Ln
Cambridge, CB2 1TN
United Kingdom

Heejun Choi

Howard Hughes Medical Institute (HHMI) - Chevy Chase - Janelia Research Campus

19700 Helix Drive
Ashburn, VA 20147
United States

Ling Hao

National Institutes of Health (NIH) - National Institute of Neurological Disorders and Stroke (NINDS)

9000 Rockville Pike
Bethesda, MD 20892
United States

Catherine M. Drerup

Government of the United States of America - National Institute of Child Health and Human Development (NICHD)

9000 Rockville Pike
Bethesda, MD 20892
United States

Seema Qamar

University of Cambridge - Cambridge Institute for Medical Research

Trinity Ln
Cambridge, CB2 1TN
United Kingdom

Jonathon Nixon-Abell

University of Cambridge - Cambridge Institute for Medical Research

Trinity Ln
Cambridge, CB2 1TN
United Kingdom

Yi Shen

University of Cambridge - Department of Chemistry

Trinity Ln
Cambridge, CB2 1TN
United Kingdom

William Meadows

University of Cambridge - Cambridge Institute for Medical Research

Trinity Ln
Cambridge, CB2 1TN
United Kingdom

Michele Vendruscolo

University of Cambridge - Department of Chemistry

Trinity Ln
Cambridge, CB2 1TN
United Kingdom

Tuomas Knowles

University of Cambridge - Department of Chemistry

Trinity Ln
Cambridge, CB2 1TN
United Kingdom

Matthew Nelson

National Institutes of Health (NIH) - National Institute of Neurological Disorders and Stroke (NINDS)

9000 Rockville Pike
Bethesda, MD 20892
United States

Magda Czekalska

University of Cambridge - Cambridge Institute for Medical Research

Trinity Ln
Cambridge, CB2 1TN
United Kingdom

Greta Musteikyte

University of Cambridge - Cambridge Institute for Medical Research

Trinity Ln
Cambridge, CB2 1TN
United Kingdom

Rajan Patel

National Institutes of Health (NIH) - National Institute of Neurological Disorders and Stroke (NINDS)

9000 Rockville Pike
Bethesda, MD 20892
United States

Christina Stephens

National Institutes of Health (NIH) - National Institute of Neurological Disorders and Stroke (NINDS)

9000 Rockville Pike
Bethesda, MD 20892
United States

Amalia Pasolli

Howard Hughes Medical Institute (HHMI) - Chevy Chase - Janelia Research Campus

19700 Helix Drive
Ashburn, VA 20147
United States

Lucy Forrest

National Institutes of Health (NIH) - National Institute of Neurological Disorders and Stroke (NINDS)

9000 Rockville Pike
Bethesda, MD 20892
United States

Peter St George-Hyslop

University of Cambridge - Cambridge Institute for Medical Research

Trinity Ln
Cambridge, CB2 1TN
United Kingdom

Jennifer Lippincott-Schwartz

Howard Hughes Medical Institute (HHMI) - Chevy Chase - Janelia Research Campus ( email )

19700 Helix Drive
Ashburn, VA 20147
United States

Michael E. Ward

National Institutes of Health (NIH) - National Institute of Neurological Disorders and Stroke (NINDS) ( email )

9000 Rockville Pike
Bethesda, MD 20892
United States

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