Arginase-II activates mTORC1 through myosin-1b in vascular cell senescence and apoptosis

Area of Science:

• Cell Biology
• Biochemistry
• Molecular Biology

Background:

• Arginase-II (Arg-II) is a Type-II hydrolase implicated in cell senescence and apoptosis.
• The mechanistic target of rapamycin complex 1 (mTORC1) pathway is crucial for cell growth and survival.
• Understanding the molecular mechanisms linking Arg-II to mTORC1 activation is essential.

Purpose of the Study:

• To elucidate the mechanism by which Arg-II activates the mTORC1 pathway.
• To identify key mediators involved in Arg-II-induced cellular changes.
• To investigate the role of myosin-1b (Myo1b) in Arg-II signaling.

Main Methods:

• Overexpression and silencing of Arg-II and Myo1b.
• Analysis of lysosomal and mTOR distribution using microscopy.
• Assessment of protein-protein interactions (TSC-lysosome).
• Investigation of Myo1b's Pleckstrin Homology (PH) domain function.
• Studies in senescent vascular smooth muscle cells.

Main Results:

• Arg-II overexpression causes lysosomal and mTOR redistribution, TSC-lysosome dissociation, and mTORC1-S6K1 activation.
• Silencing Myo1b abrogates these Arg-II-induced alterations.
• Myo1b's PH domain is critical for its association with lysosomes and its mediating role.
• Arg-II enhances Myo1b-lysosome association.
• In senescent cells, Myo1b silencing prevents Arg-II-mediated senescence and apoptosis.

Conclusions:

• Myosin-1b (Myo1b) acts as a crucial mediator for arginase-II (Arg-II)-induced mTORC1 activation.
• Myo1b facilitates peripheral lysosomal positioning, leading to TSC-lysosome dissociation and mTORC1 hyperactivation.
• This pathway contributes to cellular senescence and apoptosis, highlighting Myo1b as a potential therapeutic target.