Endocytic membrane repair by ESCRT-III controls antigen export to the cytosol during antigen cross-presentation

Gros, Marine; Ségura, Elodie; Rookhuizen, Derek C.; Baudon, Blandine; Heurtebise-Chrétien, Sandrine; Burgdorf, Nina; Kapp, Eugene A.; Simpson, Richard J.; Kozik, Patrycja; Villadangos, José A; Bertrand, Mathieu J.M.; Burbage, Marianne; Amigorena, Sebastián

doi:10.1016/j.celrep.2022.111205

Cited by 22 publications

(17 citation statements)

References 95 publications

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“…[44] Silencing of CHMP2A can lead to spontaneous necrosis. [45] Consistent with these studies, our results suggest that CHMP2A is involved in the regulation of cardiomyocyte necroptosis. Additionally, we demonstrated that CHMP2A, a transcriptional target of ATF7, participates in the regulation of cardiac injury.…”

Section: Discussionsupporting

confidence: 90%

HNEAP Regulates Necroptosis of Cardiomyocytes by Suppressing the m⁵C Methylation of Atf7 mRNA

Wang,

Li,

Zhou

et al. 2023

Advanced Science

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PIWI‐interacting RNAs (piRNAs) are highly expressed in various cardiovascular diseases. However, their role in cardiomyocyte death caused by ischemia/reperfusion (I/R) injury, especially necroptosis, remains elusive. In this study, a heart necroptosis‐associated piRNA (HNEAP) is found that regulates cardiomyocyte necroptosis by targeting DNA methyltransferase 1 (DNMT1)‐mediated 5‐methylcytosine (m5C) methylation of the activating transcription factor 7 (Atf7) mRNA transcript. HNEAP expression level is significantly elevated in hypoxia/reoxygenation (H/R)‐exposed cardiomyocytes and I/R‐injured mouse hearts. Loss of HNEAP inhibited cardiomyocyte necroptosis and ameliorated cardiac function in mice. Mechanistically, HNEAP directly interacts with DNMT1 and attenuates m5C methylation of the Atf7 mRNA transcript, which increases Atf7 expression level. ATF7 can further downregulate the transcription of Chmp2a, an inhibitor of necroptosis, resulting in the reduction of Chmp2a level and the progression of cardiomyocyte necroptosis. The findings reveal that piRNA‐mediated m5C methylation is involved in the regulation of cardiomyocyte necroptosis. Thus, the HNEAP‐DNMT1‐ATF7‐CHMP2A axis may be a potential target for attenuating cardiac injury caused by necroptosis in ischemic heart disease.

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Section: Discussionsupporting

confidence: 90%

HNEAP Regulates Necroptosis of Cardiomyocytes by Suppressing the m⁵C Methylation of Atf7 mRNA

Wang,

Li,

Zhou

et al. 2023

Advanced Science

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“…GPN is a cathepsin C substrate that induces osmotic lysis of lysosomes leading to release of lysosomal contents ( 22 ). In MutuDCs, 33 μM GPN caused endocytic damage visualised by staining for galectin 3, a marker of damaged compartments ( 23 ) (Fig. 1D).…”

Section: Main Textmentioning

confidence: 99%

Perforin-2 is a pore-forming effector of endocytic escape in cross-presenting dendritic cells

Rodríguez-Silvestre

Laub

Davies

et al. 2023

Preprint

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During initiation of antiviral and antitumour T cell-mediated immune responses, dendritic cells (DCs) cross-present exogenous antigens on MHC class I. Cross-presentation relies on the unique leakiness of endocytic compartments in DCs, whereby internalised proteins escape into the cytosol for proteasome-mediated generation of MHC I-binding peptides. Given that type 1 conventional DCs excel at cross-presentation, we searched for cell-type specific effectors of endocytic escape. We devised an escape assay suitable for genetic screening and identified a pore-forming protein, perforin-2, as a dedicated effector exclusive to cross-presenting cells. Perforin-2 is recruited to antigen-containing compartments, where it undergoes maturation, releasing its pore-forming domain. Mpeg1-/- mice fail to efficiently prime CD8+ T cells to cell-associated antigens, revealing an important role of perforin-2 in cytosolic entry of antigens during cross-presentation.

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“…S1, C and D) and that the assay recapitulates previously reported differences in escape efficiency, namely, more efficient escape in cDC1s compared with cDC2s (fig. S2, A and C) ( 18 , 21 ) and enhanced “leakiness” of endocytic compartments in cells from lupus-prone MRL/MpJ-Fas lpr /J mice (fig. S2, B and D) ( 22 ).…”

Section: A Crispr-cas9 Screen Identifies Mpeg1 (Perforin-2) As a Regu...mentioning

confidence: 99%

Perforin-2 is a pore-forming effector of endocytic escape in cross-presenting dendritic cells

Rodríguez-Silvestre

Laub

Davies

et al. 2023

Science

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During initiation of antiviral and antitumor T cell–mediated immune responses, dendritic cells (DCs) cross-present exogenous antigens on major histocompatibility complex (MHC) class I molecules. Cross-presentation relies on the unusual “leakiness” of endocytic compartments in DCs, whereby internalized proteins escape into the cytosol for proteasome-mediated generation of MHC I–binding peptides. Given that type 1 conventional DCs excel at cross-presentation, we searched for cell type–specific effectors of endocytic escape. We devised an assay suitable for genetic screening and identified a pore-forming protein, perforin-2 ( Mpeg1 ), as a dedicated effector exclusive to cross-presenting cells. Perforin-2 was recruited to antigen-containing compartments, where it underwent maturation, releasing its pore-forming domain. Mpeg1 −/− mice failed to efficiently prime CD8 + T cells to cell-associated antigens, revealing an important role for perforin-2 in cytosolic entry of antigens during cross-presentation.

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Endocytic membrane repair by ESCRT-III controls antigen export to the cytosol during antigen cross-presentation

Cited by 22 publications

References 95 publications

HNEAP Regulates Necroptosis of Cardiomyocytes by Suppressing the m⁵C Methylation of Atf7 mRNA

HNEAP Regulates Necroptosis of Cardiomyocytes by Suppressing the m⁵C Methylation of Atf7 mRNA

Perforin-2 is a pore-forming effector of endocytic escape in cross-presenting dendritic cells

Perforin-2 is a pore-forming effector of endocytic escape in cross-presenting dendritic cells

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Endocytic membrane repair by ESCRT-III controls antigen export to the cytosol during antigen cross-presentation

Cited by 22 publications

References 95 publications

HNEAP Regulates Necroptosis of Cardiomyocytes by Suppressing the m5C Methylation of Atf7 mRNA

HNEAP Regulates Necroptosis of Cardiomyocytes by Suppressing the m5C Methylation of Atf7 mRNA

Perforin-2 is a pore-forming effector of endocytic escape in cross-presenting dendritic cells

Perforin-2 is a pore-forming effector of endocytic escape in cross-presenting dendritic cells

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HNEAP Regulates Necroptosis of Cardiomyocytes by Suppressing the m⁵C Methylation of Atf7 mRNA

HNEAP Regulates Necroptosis of Cardiomyocytes by Suppressing the m⁵C Methylation of Atf7 mRNA