RESUMEN
Mixed lineage kinase-like protein (MLKL) forms amyloid-like polymers to promote necroptosis; however, the mechanism through which these polymers trigger cell death is not clear. We have determined that activated MLKL translocates to the lysosomal membrane during necroptosis induction. The subsequent polymerization of MLKL induces lysosome clustering and fusion and eventual lysosomal membrane permeabilization (LMP). This LMP leads to the rapid release of lysosomal contents into the cytosol, resulting in a massive surge in cathepsin levels, with Cathepsin B (CTSB) as a significant contributor to the ensuing cell death as it cleaves many proteins essential for cell survival. Importantly, chemical inhibition or knockdown of CTSB protects cells from necroptosis. Furthermore, induced polymerization of the MLKL N-terminal domain (NTD) also triggers LMP, leading to CTSB release and subsequent cell death. These findings clearly establish the critical role of MLKL polymerization induced lysosomal membrane permeabilization (MPI-LMP) in the process of necroptosis.
Asunto(s)
Necroptosis , Proteínas Quinasas , Proteínas Quinasas/metabolismo , Polimerizacion , Lisosomas/metabolismo , Polímeros/metabolismo , Proteína Serina-Treonina Quinasas de Interacción con Receptores/metabolismoRESUMEN
Development of novel antimicrobial agents combating drug resistance is in an urgent need. Herein we report the design and synthesis of a series of short lipo-α/sulfono-γ-AA hybrid peptides. Several short peptides exhibit potent and broad-spectrum antimicrobial activity toward both Gram-positive and Gram-negative bacteria. Membrane depolarization and fluorescence microscopy studies indicate that these short lipo-α/sulfono-γ-AA hybrid peptides can mimic the mechanisms of HDPs to kill bacteria by disrupting bacterial membranes. In addition, these short peptides also show capability to eradicate the biofilm formation of E. coli even at very low concentration. The further development of lipidated α/sulofono-γ-AA hybrid peptides may lead to a new class of antibiotic agents to combat drug resistance.