Protection from Endotoxin Shock by Selective Targeting of Proinflammatory Signaling to the Nucleus Mediated by Importin Alpha 5

Abstract

Endotoxin shock is induced by LPS, one of the most potent virulence factors of the Gram-negative bacteria that cause sepsis. It remains unknown if either proinflammatory stress-responsive transcription factors (SRTFs), ferried to nucleus by importin a5, or lipidregulating sterol regulatory element binding proteins (SREBPs), transported to the nucleus by importin b1, mediate endotoxin shock. A novel cell-penetrating peptide targeting importin a5 while sparing importin b1 protected 80% of animals from death in response to a high dose of LPS. This peptide suppresses inflammatory mediators, liver glycogen depletion, endothelial injury, neutrophil trafficking, and apoptosis caused by LPS. In D-galactosamine-pretreated mice challenged by 700-times lower dose of LPS, rapid death through massive apoptosis and hemorrhagic necrosis of the liver was also averted by the importin a5-selective peptide. Thus, using a new tool for selective suppression of nuclear transport, we demonstrate that SRTFs, rather than SREBPs, mediate endotoxin shock. ImmunoHorizons, 2019, 3: 440-446.Abbreviations used in this article: D-Gal, 2-amino-2-deoxy-D-galactosamine; HPCD, hydroxypropyl-b-cyclodextrin; Imp a, importin a; NLS, nuclear localization sequence; NTM, nuclear transport modifier; SREBP, sterol regulatory element binding protein; SSHR, signal-sequence hydrophobic region.The online version of this article contains supplemental material.

Hyperlipidemic hypersensitivity to lethal microbial inflammation and its reversal by selective targeting of nuclear transport shuttles

“…First, we compared the effect of treatment with two monoselective NTM peptides, cSN50.1α and cSN50.1β, to the effect of treatment with the biselective NTM, cSN50.1 peptide on nuclear translocation of SRTFs and MTFs in cell-based essays. Targeting Imp α5-mediated nuclear import by the monoselective NTM, cSN50.1α peptide, inhibited the nuclear translocation of NF-κB RelA, consistent with previous result in different models of microbial inflammation 30 (Fig. 2 A).…”