Endophilin A2 regulates B cell protein trafficking and humoral responses

Malinova, Dessislava; Wasim, Laabiah; Engels, Niklas; Tolar, Pavel

doi:10.1101/2020.04.20.050419

Cited by 3 publications

(3 citation statements)

References 55 publications

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“…Notably, independent new evidence has uncovered a striking connection between B cell function and EndoA2-mediated PM repair. An unbiased CRISPR screen identified EndoA2 as an important regulator of B cell-mediated humoral responses ( Malinova et al, 2020 , preprint) and B cell PM wounding and repair emerged as an antigen-triggered process that facilitates antigen uptake and presentation to T cells ( Maeda et al, 2020 , preprint).…”

Section: Discussionmentioning

confidence: 99%

Endophilin-A2 dependent tubular endocytosis promotes plasma membrane repair and parasite invasion

Corrotte

Cerasoli

Maeda

et al. 2020

Journal of Cell Science

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Endocytosis of caveolae was previously implicated in the repair of plasma membrane wounds. Here we show that caveolin-1-deficient fibroblasts lacking caveolae upregulate a tubular endocytic pathway, and have a reduced capacity to reseal after permeabilization with pore-forming toxins when compared to wild type cells. Silencing endophilin-A2 expression inhibited fission of endocytic tubules and further reduced plasma membrane repair in cells lacking caveolin-1, supporting a role for tubular endocytosis as an alternative pathway for the removal of membrane lesions. Endophilin-A2 was visualized in association with cholera toxin B-containing endosomes and was recruited to recently formed intracellular vacuoles containing Trypanosoma cruzi, a parasite that utilizes the plasma membrane wounding/repair pathway to invade host cells. Endophilin-A2 deficiency inhibited T. cruzi invasion, and fibroblasts deficient in both caveolin-1 and endophilin-A2 did not survive prolonged exposure to the parasites. These findings reveal a novel cross-talk between caveolin-1 and endophilin-A2 in the regulation of clathrin-independent endocytosis and plasma membrane repair, a process that is subverted by T. cruzi parasites for cell invasion.

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Section: Discussionmentioning

confidence: 99%

Endophilin-A2 dependent tubular endocytosis promotes plasma membrane repair and parasite invasion

Corrotte

Cerasoli

Maeda

et al. 2020

Journal of Cell Science

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“…However, B-cell resealing was inhibited when lysosomal exocytosis, a component of the PM repair response, was blocked (Reddy et al 2001). Furthermore, Endophilin A2, a protein that facilitates PM repair (Corrotte et al 2020), also contributes to BCR-mediated internalization of membrane-associated antigen (Malinova et al 2020). Finally, three different membrane-impermeable probes, PI, FM lipophilic dyes, and Ponceau 4R, gained access to the cytosol after B-cell interaction with surface-associated antigen.…”

Section: Discussionmentioning

confidence: 99%

Surface-associated antigen induces B-cell permeabilization and lysosome exocytosis facilitating antigen uptake and presentation to T-cells

Maeda

Haaren

Langley

et al. 2020

Preprint

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B-cell receptor (BCR)-mediated antigen internalization and presentation are essential for humoral memory immune responses. Antigen encountered by B-cells is often tightly associated with the surface of pathogens and/or antigen-presenting cells. Internalization of such antigens requires myosin-mediated traction forces and extracellular release of lysosomal enzymes, but the mechanism triggering lysosomal exocytosis is unknown. Here we show that BCR-mediated high-affinity recognition of antigen tethered to beads or planar lipid-bilayers causes localized plasma membrane (PM) permeabilization, a process that requires BCR signaling and non-muscle myosin II activity. B-cell permeabilization triggers a PM repair response involving lysosomal exocytosis. B-cells transiently permeabilized by surface-associated antigen internalize more antigen than cells that remain intact, and higher affinity antigens that cause more B-cell permeabilization and lysosomal exocytosis are more efficiently presented to T-cells. Thus, PM permeabilization by surface-associated antigen triggers a lysosome-mediated B-cell resealing response, which provides the extracellular hydrolases that can facilitate antigen internalization and presentation.

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“…In the last decade, we have witnessed a vertiginous development of techniques, including advanced microscopy, genome-wide screens, next-generation sequencing (NGS) and mass spectrometry (MS)-based proteomics. These techniques have allowed for the identification of several proteins and mechanisms regulating BCR activation (Awoniyi et al;Li et al, 2014;Malinova et al, 2020;Matsumoto et al, 2009;Satpathy et al, 2015). However, largely due to the easier methodology, the studies have mainly focused on the changes provoked after activation with soluble antigen, instead of the more in vivo relevant surface-bound antigen.…”

Section: Introductionmentioning

confidence: 99%

Proteomic profiling of isolated immune synapses from primary mouse B cells

Cunha

Hernández-Pérez

Awoniyi

et al. 2023

Preprint

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The immune synapse (IS) is a cell-cell interaction platform critical in lymphocyte activation by specific antigens. Despite of B cells being able to also respond to soluble antigens, in particular the in vivo importance of the IS and surface-tethered antigen recognition has strongly emerged in the recent years. The IS serves as a dynamic hub for multiple cellular actions but the molecular details of these functions, especially beyond the B cell antigen receptor (BCR) signalling, remain poorly understood. Here, to address the lack in the systems level understanding of the IS, we setup methodology for comprehensive investigation of the composition of the primary mouse B cells' IS at proteome level. Utilizing functionalized magnetic beads to mimic antigen presenting cells and trigger IS formation on them, we developed a method to specifically and robustly extract the cell adhesions on the beads, namely the IS or transferrin receptor mediated adhesion as a control. Our data revealed 661 proteins exclusively present in the IS at 15 minutes after BCR engagement, 13 exclusively in the control adhesions and 365 proteins shared between the samples. We got strong coverage of the known components of the IS as well as identified a plethora of unknown proteins and functional pathways with hitherto unknown roles in B cell IS. Thus, in this work, we validated the IS isolation method as a valuable tool to study early B cell activation by surface-bound antigens as well as unveil several novel proteins and pathways suggestive of new functional aspects in the IS.

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Endophilin A2 regulates B cell protein trafficking and humoral responses

Cited by 3 publications

References 55 publications

Endophilin-A2 dependent tubular endocytosis promotes plasma membrane repair and parasite invasion

Endophilin-A2 dependent tubular endocytosis promotes plasma membrane repair and parasite invasion

Surface-associated antigen induces B-cell permeabilization and lysosome exocytosis facilitating antigen uptake and presentation to T-cells

Proteomic profiling of isolated immune synapses from primary mouse B cells

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