8.A.210.  The Plasma Membrane Repair (PMR) Family 

Some pathogens produce pore-forming toxins (PFTs) that disrupt the plasma membrane (PM) integrity by forming transmembrane pores. High PFT concentrations cause massive damage leading to cell death and facilitating infection. Sub-lytic PFT doses activate repair mechanisms to restore PM integrity, support cell survival, and limit disease. Shedding of extracellular vesicles (EVs) is one mechanism to eliminate PFT pores and restore PM integrity. Alves et al. 2022 showed that cholesterol-dependent cytolysins (CDCs; TC# 1.C.12) are at least partially eliminated through EV release, and proteins important for PM repair are included in EVs shed by cells during repair. To identify new PM repair proteins, Alves et al. 2022 collected EVs released by cells challenged with sub-lytic doses of two different bacterial CDCs, listeriolysin O and pneumolysin and determined the EV proteomic repertoire by LC-MS/MS. Intoxicated cells release similar EVs irrespectively of the CDC used but released more and larger EVs than non-intoxicated cells. A cluster of 70 proteins, including calcium-binding proteins, molecular chaperones, cytoskeletal scaffold proteins and membrane trafficking proteins, was detected, enriched in EVs collected from intoxicated cells. While some of these proteins have well-characterized roles in repair, the involvement of others is not known. Copine-1 and Copine-3 proteins, abundantly detected in EVs released by intoxicated cells, are required for efficient repair of CDC-induced PM damage. New proteins potentially involved in PM repair were described, and they gave new insights into common mechanisms and machinery engaged by cells in response to PM damage (Alves et al. 2022).

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