ARL8 Relieves SKIP Autoinhibition to Enable Coupling of Lysosomes to Kinesin-1

Keren-Kaplan, Tal; Bonifacino, Juan S.

doi:10.1016/j.cub.2020.10.071

Cited by 52 publications

(57 citation statements)

References 75 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Further analyses demonstrated that both RUFY3 and RUFY4 interact with the GTP-bound form of ARL8 and are recruited to lysosomes in an ARL8-dependent manner. Although ARL8 was previously shown to bind to the RUN domains of SKIP and PLEKHM1 (Farias et al, 2017;Keren-Kaplan and Bonifacino, 2021;Marwaha et al, 2017;Rosa-Ferreira and Munro, 2011), we find that binding of ARL8 to RUFY3 involves the CC2 domain of RUFY3. These observations imply that ARL8 can bind its effectors by different mechanisms.…”

Section: Discussioncontrasting

confidence: 81%

“…Interaction with ARL8 was inferred from relocalization of the RUFY3 constructs to mitochondria. By analogy with SKIP, which interacts with ARL8 via the RUN domain (Boucrot et al, 2005;Keren-Kaplan and Bonifacino, 2021;Rosa-Ferreira and Munro, 2011), we expected the homologous RUN domain of RUFY3 to be important. However, we found that deletion of the RUN, CC1 or FYVE domains had no effect on the re-localization of RUFY3-GFP to mitochondria (Fig.…”

Section: The Cc2 Domain Of Rufy3 Is Required For Binding To Arl8mentioning

confidence: 99%

“…The interaction of ARL8-GTP with HOPS promotes fusion of lysosomes with late endosomes (Khatter et al, 2015a;Marwaha et al, 2017), phagosomes (Garg et al, 2011), autophagosomes (Jia et al, 2017) and Salmonella-containing vacuoles (Sindhwani et al, 2017), in some cases in cooperation with PLEKHM1 (Marwaha et al, 2017). The interaction of ARL8-GTP with SKIP mediates recruitment of the kinesin-1 motor protein (KIF5 2 -KLC 2 ) for anterograde transport of lysosomes toward the peripheral cytoplasm in non-polarized cells (Guardia et al, 2016;Keren-Kaplan and Bonifacino, 2021;Pu et al, 2015;Rosa-Ferreira and Munro, 2011;Tuli et al, 2013) and the distal axon in neurons (Farias et al, 2017;Rosa-Ferreira et al, 2018;Vukoja et al, 2018). The ARL8-SKIP-kinesin-1 ensemble is also responsible for the formation of tubular lysosomes in lipopolysaccharide-treated macrophages (Mrakovic et al, 2012) and in the process of phagolysosome resolution (Levin-Konigsberg et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

Keren-Kaplan¹,

Sarić²,

Ghosh³

et al. 2021

Preprint

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Discussioncontrasting

confidence: 81%

Section: The Cc2 Domain Of Rufy3 Is Required For Binding To Arl8mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

Keren-Kaplan¹,

Sarić²,

Ghosh³

et al. 2021

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…Arl8b overexpression was shown to increase the proportion of lysosomes undergoing bi-directional long-range movement on the microtubule tracks (Hofmann and Munro, 2006). Subsequent studies revealed that Arl8b binds to effector protein PLEKHM2 (also known as SKIP), which in turn binds and recruits kinesin-1 motor to promote anterograde motility of lysosomes (Keren-Kaplan and Bonifacino, 2021;Pu et al, 2015;Rosa-Ferreira and Munro, 2011;Tuli et al, 2013). However, it was not known whether Arl8b could mediate long-range retrograde movement of lysosomes.…”

Section: Discussionmentioning

confidence: 99%

“…2F) (Garg et al, 2011;Hofmann and Munro, 2006;Khatter et al, 2015a;Khatter et al, 2015b). This is attributed to Arl8b interaction with a RUN domain-containing protein, SKIP that binds and recruits, kinesin-1 motor to drive the anterograde motility of late endosome/lysosome (LE/Lys) on microtubule tracks (Keren-Kaplan and Bonifacino, 2021;Rosa-Ferreira and Munro, 2011). Interestingly, co-expression of RUFY3 caused a striking shift in Arl8b distribution to the perinuclear region wherein both proteins colocalized on these perinuclear compartments (see inset, Fig.…”

Section: Rufy3 Is An Arl8b Effector That Localizes To Lysosomesmentioning

confidence: 95%

RUFY3 links Arl8b and JIP4-Dynein complex to regulate lysosome size and positioning

Kumar¹,

Chawla²,

Chadha³

et al. 2021

Preprint

View full text Add to dashboard Cite

The whole-cell scale spatial organization of lysosomes is regulated by their bidirectional motility on microtubule tracks. Small GTP-binding (G) protein, Arl8b, stimulates the anterograde transport of lysosomes by recruiting adaptor protein SKIP (also known as PLEKHM2), which in turn couples the microtubule motor kinesin-1. Here, we have identified an Arl8b effector, RUN and FYVE domain-containing protein family member 3, RUFY3, which drives the retrograde transport of lysosomes. Artificial targeting of RUFY3 to the surface of mitochondria was sufficient to drive their perinuclear positioning. We find that RUFY3 interacts with the JIP4-Dynein-Dynactin complex and mediates Arl8b association with the retrograde motor complex. The mobile fraction of the total lysosomes per cell was significantly enhanced upon RUFY3 depletion, suggesting that RUFY3 maintains the lysosomes clustering within the perinuclear cloud. Expectedly, RUFY3 knockdown disrupted the perinuclear positioning of lysosomes upon nutrient starvation and/or serum depletion, although lysosome continued to undergo fusion with autophagosomes. Interestingly, lysosome fission events were more frequent in RUFY3-depleted cells and accordingly, there was a striking reduction in lysosome size, an effect that was also observed in dynein and JIP4 depleted cells. These findings indicate that the dynein-dependent “perinuclear cloud” arrangement of lysosomes also regulates the size of these proteolytic compartments and, likely, their cellular roles.

show abstract

The Arf family GTPases: Regulation of vesicle biogenesis and beyond

Guan

2023

BioEssays

View full text Add to dashboard Cite

The Arf family proteins are best known for their roles in the vesicle biogenesis. However, they also play fundamental roles in a wide range of cellular regulation besides vesicular trafficking, such as modulation of lipid metabolic enzymes, cytoskeleton remodeling, ciliogenesis, lysosomal, and mitochondrial morphology and functions. Growing studies continue to expand the downstream effector landscape of Arf proteins, especially for the less‐studied members, revealing new biological functions, such as amino acid sensing. Experiments with cutting‐edge technologies and in vivo functional studies in the last decade help to provide a more comprehensive view of Arf family functions. In this review, we summarize the cellular functions that are regulated by at least two different Arf members with an emphasis on those beyond vesicle biogenesis.

show abstract

ARL8 Relieves SKIP Autoinhibition to Enable Coupling of Lysosomes to Kinesin-1

Cited by 52 publications

References 75 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

RUFY3 links Arl8b and JIP4-Dynein complex to regulate lysosome size and positioning

The Arf family GTPases: Regulation of vesicle biogenesis and beyond

Contact Info

Product

Resources

About