Patch repair protects cells from the small pore-forming toxin aerolysin

Thapa, Roshan; Keyel, Peter A.

doi:10.1101/2022.09.22.509098

Cited by 2 publications

(1 citation statement)

References 45 publications

(177 reference statements)

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“…A2tet interacts with actin, which provides a scaffold for the recruitment of other membrane repair proteins, including the patch repair protein dysferlin 24,28 (Figure 1). Dysferlinpositive vesicles fuse with the membrane during repair, 29 supporting dysferlin cross-linking membranes to promote patch repair. However, dysferlin is also present on the plasma membrane, so this could be the source of dysferlin during repair instead.…”

Section: Contribution Of Annexin A2 To Membrane Repairmentioning

confidence: 94%

Translational implications of targeting annexin A2: From membrane repair to muscular dystrophy, cardiovascular disease and cancer

Kayejo,

Fellner,

Thapa

et al. 2023

Clinical and Translational Dis

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BackgroundAnnexin A2 contributes to several key cellular functions and processes, including membrane repair. Effective repair prevents cell death and degeneration, especially in skeletal or cardiac muscle, epithelia, and endothelial cells. To maintain cell integrity after damage, mammalian cells activate multiple membrane repair mechanisms. One protein family that facilitates membrane repair processes are the Ca2+‐regulated phospholipid‐binding annexins.BodyAnnexin A2 facilitates repair in association with S100A10 and related S100 proteins by forming a plug and linking repair to other physiologic functions. Deficiency of annexin A2 enhances cellular degeneration, exacerbating muscular dystrophy and degeneration. Downstream of repair, annexin A2 links the membrane with the cytoskeleton, calcium‐dependent endocytosis, exocytosis, cell proliferation, transcription, and apoptosis to extracellular roles, including vascular fibrinolysis, and angiogenesis. These roles regulate cardiovascular disease progression. Finally, annexin A2 protects cancer cells from membrane damage due to immune cells or chemotherapy. Since these functions are regulated by post‐translational modifications, they represent a therapeutic target for reducing the negative consequences of annexin A2 expression.ConclusionThus, connecting the roles of annexin A2 in repair to its other physiologic functions represents a new translational approach to treating muscular dystrophy and cardiovascular diseases without enhancing its pro‐tumorigenic activities.

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Section: Contribution Of Annexin A2 To Membrane Repairmentioning

confidence: 94%

Translational implications of targeting annexin A2: From membrane repair to muscular dystrophy, cardiovascular disease and cancer

Kayejo,

Fellner,

Thapa

et al. 2023

Clinical and Translational Dis

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Pathogenic Mutations in the C2A Domain of Dysferlin form Amyloid that Activates the Inflammasome

Scott

Dominguez

Snow

et al. 2023

Preprint

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Limb-Girdle Muscular Dystrophy Type-2B/2R is a condition that arises due to mutations in the dysferlin gene (DYSF). This disease has two known pathogenic missense mutations that occur within the C2A domain, namely C2A-W52R, and C2A-V67D. Yet, the etiological rationale to explain the disease linkage for these two mutations is still unclear. In this study, we have presented evidence from biophysical, computational, and immunological experiments which suggest that these missense mutations interfere with dysferlin's ability to repair cells. The failure of C2A W52R and C2A-V67D to initiate membrane repair arises from their propensity to form stable amyloid. The misfolding of the C2A domain caused by either mutation exposes β strands, which are predicted to nucleate classical amyloid structures. When dysferlin C2A amyloid is formed, it triggers the NLRP3 inflammasome, leading to the secretion of inflammatory cytokines, including IL-1β. The present study suggests that the muscle dysfunction and inflammation evident in Limb-Girdle Muscular Dystrophy types-2B/2R, specifically in cases involving V67D and W52R mutations, as well as other C2 domain mutations with considerable hydrophobic core involvement, may be attributed to this mechanism.

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Patch repair protects cells from the small pore-forming toxin aerolysin

Cited by 2 publications

References 45 publications

Translational implications of targeting annexin A2: From membrane repair to muscular dystrophy, cardiovascular disease and cancer

Translational implications of targeting annexin A2: From membrane repair to muscular dystrophy, cardiovascular disease and cancer

Pathogenic Mutations in the C2A Domain of Dysferlin form Amyloid that Activates the Inflammasome

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