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Connexin43 promotes exocytosis of damaged lysosomes through actin remodelling

Domingues, Neuza, Catarino, Steve, Cristóvão, Beatriz, Rodrigues, Lisa, Carvalho, Filomena A, Sarmento, Maria João, Zuzarte, Mónica, Almeida, Jani, Ribeiro-Rodrigues, Teresa, Correia-Rodrigues, Ânia, Fernandes, Fábio, Rodrigues-Santos, Paulo, Aasen, Trond, Santos, Nuno C, Korolchuk, Viktor I, Gonçalves, Teresa, Milosevic, Ira, Raimundo, Nuno, Girão, Henrique·2024·The EMBO Journal
DOI 10.1038/s44318-024-00177-3PMC PMC11377567
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Abstract

A robust and efficient cellular response to lysosomal membrane damage prevents leakage from the lysosome lumen into the cytoplasm. This response is understood to happen through either lysosomal membrane repair or lysophagy. Here we report exocytosis as a third response mechanism to lysosomal damage, which is further potentiated when membrane repair or lysosomal degradation mechanisms are impaired. We show that Connexin43 (Cx43), a protein canonically associated with gap junctions, is recruited from the plasma membrane to damaged lysosomes, promoting their secretion and accelerating cell recovery. The effects of Cx43 on lysosome exocytosis are mediated by a reorganization of the actin cytoskeleton that increases plasma membrane fluidity and decreases cell stiffness. Furthermore, we demonstrate that Cx43 interacts with the actin nucleator Arp2, the activity of which was shown to be necessary for Cx43-mediated actin rearrangement and lysosomal exocytosis following damage. These results define a novel mechanism of lysosomal quality control whereby Cx43-mediated actin remodelling potentiates the secretion of damaged lysosomes.

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  • Impaired degradation leads to lysosomal stress and could prompt cells to rid themselves of undigested cargo via other mechanisms.

    “Impaired degradation leads to lysosomal stress and could prompt cells to rid themselves of undigested cargo via other mechanisms (Domingues et al. 2024; Wang, Telpoukhovskaia, et al. 2018; Zhong et al. 2023).”

    From The Alzheimer's Disease Gene SORL1 Regulates Lysosome Function in Human Microglia (2025) · cites this paper as Domingues et al. 2024

    The Results section (‘Exocytosis is involved in cellular response to lysosomal injury’; page unavailable) reports that impaired lysophagy in cells with damaged lysosomes increased lysosomal exocytosis, supporting an alternative disposal route. The paper does not show that impaired degradation itself causes lysosomal stress or that the material expelled is undigested cargo; it studies the disposal of damaged lysosomes and secretion of lysosomal contents. (LLM, conf=0.85)

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Metadata

Authors
Domingues, N., Catarino, S., Cristóvão, B., Rodrigues, L., Carvalho, F. A., Sarmento, M. J., Zuzarte, M., Almeida, J., Ribeiro-Rodrigues, T., Correia-Rodrigues, Â., Fernandes, F., Rodrigues-Santos, P., Aasen, T., Santos, N. C., Korolchuk, V. I., Gonçalves, T., Milosevic, I., Raimundo, N., & Girão, H.
ORCID
Venue
The EMBO Journal
Publisher
Springer Science and Business Media LLC
Published
2024-07-23
Volume
43
Issue
17
Pages
3627-3649
ISSN
1460-2075
DOI
10.1038/s44318-024-00177-3
PMC
PMC11377567
Cited by
28
References
2
Language
en
Licence
Funders
  • MEC | Fundação para a Ciência e a Tecnologia (PPBI-POCI-01-0145-FEDER-022122, UIDB/04539/2020, UIDP/04539/2020, FCT-PTDC/MED-NEU/8030/2020, FCT-2022.09311)
  • 'la Caixa' Foundation (Synageing HR22-00854)
  • EC | Horizon 2020 Framework Programme (857524)
  • EC | European Regional Development Fund (Comissão de Coordenação e Desenvolvimento Regional do Centro - CCDRC through the Centro2020 Programm)
  • John Black Charitable Foundation
  • Wellcome Trust (224361/Z/21/Z)

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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