Journal
BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES
Volume 1862, Issue 3, Pages -Publisher
ELSEVIER
DOI: 10.1016/j.bbamem.2019.183155
Keywords
Cell-penetrating peptides; Calcium; Orai; Glycosylation; Drug delivery
Categories
Funding
- Brazilian research funding agency CAPES (Coordenacao de Aperfeicoamento Pessoal de Nivel Superior) [BEX 13247/13-1]
- Roche postdoc programme [RPF 272]
- Radboud Scholarship Programme
- Radboudumc Study Fund
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At concentrations exceeding 10 mu M, arginine-rich cell-penetrating peptides (CPPs) trigger a rapid cytoplasmic import that involves activation of acid sphingomyelinase (ASMase). ASMase activation occurs through a variety of stress signals and has also been related to the reorganization of membrane microdomains during entry of pathogens. However, in none of these cases has the initial trigger for ASMase activation been established on a molecular level. We here show that rapid cytosolic CPP import depends upon an increase in intracellular calcium, likely caused by modulation of the Orai1 calcium channel. At low peptide concentration, cytoplasmic import could be induced by thapsigargin, a known activator of Orai1. Compounds known to block Orai1 inhibited rapid uptake. Peptide-mediated modulation of Orai1 involved cell surface sialic acids as inhibition of sialylation as well as chemical blocking of sialic acids reduced rapid cytoplasmic uptake, which could be reconstituted by thapsigargin. These results establish a link between the known propensity of arginine-rich CPPs to interact with the glycocalyx and calcium influx as the initial step triggering direct cytosolic peptide uptake.
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