Neuronally Enriched RUFY3 Is Required for Caspase-Mediated Axon Degeneration

Hertz, Nicholas T.; Adams, Eliza L.; Weber, Ross A.; Shen, Rebecca; O’Rourke, Melanie K.; Simon, David; Zebroski, Henry; Olsen, Olav; Morgan, Charles W.; Mileur, Trevor R.; Hitchcock, Angela M.; Armstrong, Nicholas A. Sinnott; Wainberg, Michael; Bassik, Michael C.; Molina, Henrik; Wells, James A.; Tessier‐Lavigne, Marc

doi:10.1016/j.neuron.2019.05.030

Cited by 16 publications

(15 citation statements)

References 46 publications

(72 reference statements)

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“…Both forms arise by alternative splicing of the RUFY3 pre-mRNA. The short form had been shown to be particularly abundant in the brain, and to play roles in neuronal polarity and the regulation of axon specification, growth and degeneration (Hertz et al, 2019;Honda et al, 2017;Mori et al, 2007;Wei et al, 2014). The existence, distribution and function of the long form had not been previously documented.…”

Section: Discussionmentioning

confidence: 99%

“…1d). The shorter RUFY3.2 is the only RUFY3 spliceform characterized to date; previous studies showed that it plays roles in neuronal polarity and axon formation and degeneration (Hertz et al, 2019;Honda et al, 2017;Mori et al, 2007;Wei et al, 2014), and in cancer cell migration, invasion and metastasis (Men et al, 2019;Wang et al, 2015;Xie et al, 2017;Zhu et al, 2019). Protein and mRNA expression databases (e.g., https://www.proteinatlas.org/) indicate that RUFY3 is expressed in all cells and tissues, Keren-Kaplan et al…”

Section: Identification Of Rufy3 and Rufy4 As Arl8 Effectorsmentioning

confidence: 99%

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RUFY3 and RUFY4 are ARL8 effectors that couple lysosomes to dynein-dynactin

Keren-Kaplan¹,

Sarić²,

Ghosh³

et al. 2021

Preprint

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The small GTPase ARL8 associates with lysosomes and recruits several effectors that mediate coupling to kinesins for anterograde transport, as well as tethering for eventual fusion with other organelles. Herein we report the identification of the “RUN- and FYVE-domain-containing” proteins RUFY3 and RUFY4 as novel ARL8 effectors that couple lysosomes to dynein-dynactin for retrograde transport. Using various biochemical approaches, we find that RUFY3/4 interact with both GTP-bound ARL8 and dynein-dynactin. In addition, we show that RUFY3/4 are both necessary and sufficient for concentration of lysosomes in the juxtanuclear area of the cell. RUFY3/4 also promote retrograde transport of lysosomes in the axon of hippocampal neurons. The function of RUFY3/4 in retrograde transport is required for juxtanuclear redistribution of lysosomes upon serum starvation or cytoplasmic alkalinization, and may underlie the reported roles of RUFY3/4 in axon development/degeneration, cancer and immunity. These studies thus establish RUFY3/4 as novel ARL8-dependent, dynein-dynactin adaptors, and highlight the role of ARL8 in the regulation of both anterograde and retrograde lysosome transport.

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Section: Discussionmentioning

confidence: 99%

Section: Identification Of Rufy3 and Rufy4 As Arl8 Effectorsmentioning

confidence: 99%

RUFY3 and RUFY4 are ARL8 effectors that couple lysosomes to dynein-dynactin

Keren-Kaplan¹,

Sarić²,

Ghosh³

et al. 2021

Preprint

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“…Olfactory dysfunction occurs in 90% of AD cases and is correlated with elevated rufy3 expression in glomerular and mitral layers of the olfactory bulb ( Zelaya et al, 2015 ). RUFY3 is cleaved by caspase 3 and critically required for caspase-mediated degeneration of tropomyosin receptor kinase A positive sensory axons in vitro and in vivo ( Hertz et al, 2019 ; Figure 4C ). Removal of neuronally enriched RUFY3 is able to block caspase 3-dependent apoptosis, while dephosphorylation of RUFY3 at residue S34 appears required for its degradation ( Hertz et al, 2019 ).…”

Section: Rufy3mentioning

confidence: 99%

“…RUFY3 is cleaved by caspase 3 and critically required for caspase-mediated degeneration of tropomyosin receptor kinase A positive sensory axons in vitro and in vivo ( Hertz et al, 2019 ; Figure 4C ). Removal of neuronally enriched RUFY3 is able to block caspase 3-dependent apoptosis, while dephosphorylation of RUFY3 at residue S34 appears required for its degradation ( Hertz et al, 2019 ). Analysis of rufy3 -deficient mice supports a second distinct function for RUFY3 in neuronal growth and polarity, since mutant embryos show defects in axonal projection patterns.…”

Section: Rufy3mentioning

confidence: 99%

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The RUFYs, a Family of Effector Proteins Involved in Intracellular Trafficking and Cytoskeleton Dynamics

Char

Pierre

2020

Front. Cell Dev. Biol.

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Intracellular trafficking is essential for cell structure and function. In order to perform key tasks such as phagocytosis, secretion or migration, cells must coordinate their intracellular trafficking, and cytoskeleton dynamics. This relies on certain classes of proteins endowed with specialized and conserved domains that bridge membranes with effector proteins. Of particular interest are proteins capable of interacting with membrane subdomains enriched in specific phosphatidylinositol lipids, tightly regulated by various kinases and phosphatases. Here, we focus on the poorly studied RUFY family of adaptor proteins, characterized by a RUN domain, which interacts with small GTP-binding proteins, and a FYVE domain, involved in the recognition of phosphatidylinositol 3-phosphate. We report recent findings on this protein family that regulates endosomal trafficking, cell migration and upon dysfunction, can lead to severe pathology at the organismal level.

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An atlas of caspase cleavage events in differentiating muscle cells

Gomez‐Cardona,

Dehkordi,

Van Baar

et al. 2024

Protein Science

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Executioner caspases, such as caspase‐3, are known to induce apoptosis, but in other contexts, they can control very different fates, including cell differentiation and neuronal plasticity. While hundreds of caspase substrates are known to be specifically targeted during cell death, we know very little about how caspase activity brings about non‐apoptotic fates. Here, we report the first proteome identification of cleavage events in C2C12 cells undergoing myogenic differentiation and its comparison to undifferentiated or dying C2C12 cells. These data have identified new caspase substrates, including caspase substrates specifically associated with differentiation, and show that caspases are regulating proteins involved in myogenesis in myotubes, several days after caspase‐3 initiated differentiation. Cytoskeletal proteins emerged as a major group of non‐apoptotic caspase substrates. We also identified proteins with well‐established roles in muscle differentiation as substrates cleaved in differentiating cells.

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Neuronally Enriched RUFY3 Is Required for Caspase-Mediated Axon Degeneration

Cited by 16 publications

References 46 publications

RUFY3 and RUFY4 are ARL8 effectors that couple lysosomes to dynein-dynactin

RUFY3 and RUFY4 are ARL8 effectors that couple lysosomes to dynein-dynactin

The RUFYs, a Family of Effector Proteins Involved in Intracellular Trafficking and Cytoskeleton Dynamics

An atlas of caspase cleavage events in differentiating muscle cells

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