title: A subset of membrane-altering agents and γ-secretase modulators provoke nonsubstrate cleavage by rhomboid proteases.
abstract: Rhomboid proteases are integral membrane enzymes that regulate cell signaling, adhesion, and organelle homeostasis pathways, making substrate specificity a key feature of their function. Interestingly, we found that perturbing the membrane pharmacologically in living cells had little effect on substrate processing but induced inappropriate cleavage of nonsubstrates by rhomboid proteases. A subclass of drugs known to modulate γ-secretase activity acted on the membrane directly and induced nonsubstrate cleavage by rhomboid proteases but left true substrate cleavage sites unaltered. These observations highlight an active role for the membrane in guiding rhomboid selectivity and caution that membrane-targeted drugs should be evaluated for cross-activity against membrane-resident enzymes that are otherwise unrelated to the intended drug target. Furthermore, some γ-secretase-modulating activity or toxicity could partly result from global membrane effects.
authors.affiliation: Howard Hughes Medical Institute, Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: surban@jhmi.edu.
authors.forename: Siniša
authors.initials: S
authors.lastname: Urban
authors.affiliation: Howard Hughes Medical Institute, Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Syed M
authors.initials: SM
authors.lastname: Moin
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D002462:Cell Membrane / Q000187:drug effects* / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D059748:Proteolysis; D012697:Serine Endopeptidases / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*
chemical_list: D015842:Serine Proteinase Inhibitors; D053829:Amyloid Precursor Protein Secretases; D012697:Serine Endopeptidases