Actin-dependent endosomal receptor recycling

Simonetti, Boris; Cullen, Peter J.

doi:10.1016/j.ceb.2018.08.006

Cited by 102 publications

(114 citation statements)

References 105 publications

(200 reference statements)

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“…First, Arp2/3 may act at the endosome to promote anterograde sterol transfer, such that its inhibition leads to a retention of sterols in endosomes. In support of this, Arp2/3 is well-established to localize to endosomes and play numerous roles in cargo sorting and membrane fission in mammalian cells (Simonetti and Cullen, 2019). The spherical shape of STRIC post CK-666 treatment, which contrasts with the more varied shapes of Syb1-positive organelles in untreated cells, also suggests that Arp2/3dependent actin nucleation may contribute to membrane deformation on the endosome also in yeast cells.…”

Section: Why Does Arp2/3 Inhibition Lead To Sterol Accumulation In Enmentioning

confidence: 81%

Sterol flow between the plasma membrane and the endosome is regulated by the LAM family protein Ltc1

Marek

Vincenzetti

2019

Preprint

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Sterols are crucial components of biological membranes that help maintain membrane integrity and regulate various processes such as endocytosis, protein oligomerization and signaling. Although synthetized in the ER, sterols are at highest concentrations at the plasma membrane (PM) in all eukaryotic organisms. Here, by applying a genetically encoded sterol biosensor (D4H), we visualize a sterol flow between PM and endosomes in the fission yeast Schizosaccharomyces pombe. While D4H is detected at the PM during steady-state growth, inhibition of Arp2/3-dependent F-actin assembly unexpectedly promotes the reversible re-localization of the probe to internal sterol rich compartments (STRIC), as shown by correlative light-electron microscopy. Time-lapse imaging identifies STRIC as a late secretory, endosomal compartment labelled by the synaptobrevin Syb1. Retrograde sterol internalization to STRIC is independent of endocytosis or an intact Golgi. Instead, it depends on Ltc1, a LAM/StARkin-family protein that localizes to ER-PM contact sites. In ltc1Δ, sterols over-accumulate at the PM, which forms extended ER-interacting invaginations, indicating that sterol transfer by Ltc1 contributes to PM size homeostasis. Anterograde sterol movement from STRIC is independent of canonical vesicular trafficking components but requires Arp2/3 activity, suggesting a novel physiological role for this complex. Thus, transfer routes orthogonal to vesicular trafficking govern the retrograde and anterograde flow of sterols in the cell.

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Section: Why Does Arp2/3 Inhibition Lead To Sterol Accumulation In Enmentioning

confidence: 81%

Sterol flow between the plasma membrane and the endosome is regulated by the LAM family protein Ltc1

Marek

Vincenzetti

2019

Preprint

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“…By binding to WASP proteins, ITSN2-L facilitates Cdc42-dependent actin polymerization (Klein et al, 2009;McGavin et al, 2001). Actin polymerization may act as a scaffold to limit cargo diffusion on endosomes and control their fate (Simonetti and Cullen, 2019). In contrast to Cdc42, RhoU does not interact with the GTPase binding domain of WASP (Saras et al, 2004) and among RhoU effector, none has been reported to mediate actin polymerization.…”

Section: Our Findings Question Whether Rhou Activities Might Be Regulmentioning

confidence: 99%

The atypical Rho GTPase RhoU interacts with Intersectin-2 to regulate endosomal recycling pathways

Gubar

Croisé

Kropyvko

et al. 2019

Preprint

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Rho GTPases play a key role in various membrane trafficking processes. RhoU is an atypical small Rho GTPase related to Rac/Cdc42 which possesses unique N-and C-terminal domains that regulate its function and its subcellular localization. RhoU localized at the plasma membrane, on endosomes and in cell adhesion structures where it governs cell signalling, differentiation and migration. However, despite its endomembrane localization, RhoU function in vesicular trafficking has been unexplored. Here, we identified intersectins (ITSNs) as new binding partners for RhoU and showed that the second PxxP motif at the Nterminus of RhoU mediated interactions with SH3 domains of ITSNs. To evaluate the function of RhoU and ITSNs in vesicular trafficking, we used fluorescent transferrin as a cargo for uptake experiments. We showed that silencing of either RhoU or ITSN2, but not ITSN1 increased transferrin accumulation in early endosomes resulting from defect in fast vesicle recycling. Concomitantly, RhoU and ITSN2 colocalized to a subset of Rab4-positive vesicles suggesting that RhoU-ITSN2 interaction may occur on fast recycling endosomes to regulate the fate of vesicular cargos. Corvera, S. (2008). Sorting of EGF and Transferrin at the plasma membrane and by cargo-specific signaling to EEA1-enriched endosomes.

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“…Dynamic rearrangement of the actin cytoskeleton is a critical component in generating tubular membrane systems (Gautreau et al, 2014;Simonetti and Cullen, 2019) . It relies on the capacity of actin filaments to polymerize and depolymerize, a characteristic that can be influenced by the ability of DBN to bind the lateral filament surface, to bundle actin filaments and to inhibit actin nucleation (Ginosyan et al, 2019;Grintsevich et al, 2010;Li et al, 2019).…”

Section: Dbn Generates Tubular Endosomes By Counteracting Arp2/3-depementioning

confidence: 99%

“…Membrane tubulation occurs particularly on maturing early endosomes and macropinosomes to separate components from the quick 'bulk flow' back to the plasma membrane and to direct them towards other compartments such as the Golgi network or recycling endosomes (Naslavsky and Caplan, 2018). The actin cytoskeleton creates stable tubular subdomains, where membrane-bound cargos segregate and concentrate according to their designated destinations (Bowman et al, 2016;Puthenveedu et al, 2010;Simonetti and Cullen, 2019). We propose a role for DBN in inwarddirected RAB8-based membrane trafficking: upon wounding, DBN may contribute to the uptake of plasma membrane material by compiling endocytosed receptors and material in the injury-induced RAB8-compartment that are essentially sorted by DBN-stabilized tubules ( Figure 7).…”

Section: Dbn Functions As An Injury-induced Actin Regulator In Membramentioning

confidence: 99%

Drebrin mediates scar formation and astrocyte reactivity during brain injury by inducing RAB8 tubular endosomes

Schiweck

Murk

Ledderose

et al. 2020

Preprint

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The brain of mammals lacks a significant ability to regenerate neurons and is thus particularly vulnerable. To protect the brain from injury and disease, damage control by astrocytes through astrogliosis and scar formation is vital. Here, we show that brain injury triggers an ad hoc upregulation of the actin-binding protein Drebrin (DBN) in astrocytes, which is essential for the formation and maintenance of glial scars in vivo. In turn, DBN loss leads to defective glial scar formation and excessive neurodegeneration following mild brain injuries. At the cellular level, DBN switches actin homeostasis from ARP2/3-dependent arrays to microtubule-compatible scaffolds and facilitates the formation of RAB8-positive membrane tubules. This injury-specific RAB8 membrane compartment serves as hub for the trafficking of surface proteins involved in astrogliosis and adhesive responses, such as β1integrin. Our work identifies DBN as pathology-specific actin regulator, and establishes DBNdependent membrane trafficking as crucial mechanism in protecting the brain from escalating damage following traumatic injuries. MAINThe brain of higher mammals is vulnerable to traumatic injury and disease, but largely lacks the capacity to regenerate neurons and rarely regains function in damaged areas (Barker et al., 2018). This makes the containment of local pathological incidents critical to avoid the propagation of inflammation and neurodegeneration into the uninjured brain parenchyma.Astrocytes are key players in protection of CNS tissue via a defense mechanism known as reactive astrogliosis. This process is associated with comprehensive changes in astrocyte morphology and function (Schiweck et al., 2018). Reactive astrocytes develop hypertrophies of soma and protrusions, while cells in proximity to large lesion sites polarize and extend particularly long processes. Dense arrays of such 'palisades' and hypertrophic astrocytes constitute glial scars, which enclose as physical barriers inflammatory cues and extravasating leucocytes, and limit the spread of damage (Faulkner et al., 2004;Frik et al., 2018). Glial scars are anatomically well described, but the molecular details controlling astrocyte reactivity are still poorly understood.In the context of astrogliosis and scar formation, we studied drebrin (DBN), a cytoskeletal regulator, which stabilizes actin filaments by sidewise binding and by competing off other actin binding proteins (Grintsevich et al., 2010;Mikati et al., 2013). It is widely expressed, but has mainly been studied in neurons (Aoki et al., 2005). In cultured astrocytes, DBN has been described to maintain connexin 43 at the plasma membrane (Butkevich et al., 2004).Functional coupling of astrocytes into networks through gap junctions is essential to modulate neuronal transmission (He et al., 2020;Pannasch and Rouach, 2013). A deficit in DBN would therefore be expected to cause profound phenotypes in vivo. However, mouse models with acute or chronic DBN loss indicate non-essential functions of this actin binding protein d...

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Actin-dependent endosomal receptor recycling

Cited by 102 publications

References 105 publications

Sterol flow between the plasma membrane and the endosome is regulated by the LAM family protein Ltc1

Sterol flow between the plasma membrane and the endosome is regulated by the LAM family protein Ltc1

The atypical Rho GTPase RhoU interacts with Intersectin-2 to regulate endosomal recycling pathways

Drebrin mediates scar formation and astrocyte reactivity during brain injury by inducing RAB8 tubular endosomes

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