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Alterations in Plasma Membrane Ion Channel Structures Stimulate NLRP3 Inflammasomes Activation in APOL1 Risk Milieu.

著者 Jha A , Kumar V , Haque S , Ayasolla K , Saha S , Lan X , Malhotra A , Saleem MA , Skorecki K , Singhal PC
FEBS J.2019 Nov 12 ; ():.
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We evaluated alterations in the structural configurations of channels and activation of NLRP3 inflammasomes formation in APOL1 risk and non-risk milieus. APOL1G1- and APOL1G2- expressing podocytes displayed enhanced K efflux, induction of pyroptosis, and escalated transcription of interleukin (IL)-1β and IL-18. APOL1G1- and APOL1G2-expressing podocytes promoted the transcription as well as translation of proteins involved in the formation of inflammasomes. Since glyburide (a specific inhibitor of K efflux channels) inhibited the transcription of NLRP3, IL-1β, and IL-18, the role of K efflux in the activation of inflammasomes in APOL1 risk milieu was implicated. To evaluate the role of structural alterations in K channels in plasma membranes, bioinformatics studies, including molecular dynamic (MD) simulation were carried out. Superimposition of bioinformatics reconstructions of APOL1G0, G1, and G2 showed several aligned regions. The analysis of pore-lining residues revealed that Ser342 and Tyr389 are involved in APOL1G0 pore formation and the altered conformations resulting from the Ser342Gly and Ile384Met mutation in the case of APOLG1 and deletion of the Tyr389 residue in the case of APOL1G2 are expected to alter pore characteristics, including K ion selectivity. Analysis of multiple membrane (lipid bilayer) models of interaction with the peripheral protein, integral membrane protein, and multimer protein revealed that for an APOL1 multimer model, APOL1G0 is not energetically favorable while the APOL1G1 and APOL1G2 moieties favor the insertion of multiple ion channels into the lipid bilayer. We conclude that altered pore configurations carry the potential to facilitate K ion transport in APOL1 risk milieu.
PMID: 31714001 [PubMed - as supplied by publisher]
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