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1.D.279.  The Lysosomal Membrane Permeabilization LLOMe Dipeptide (LLOMe) Family 

Endosomal-lysosomal trafficking is accompanied by the acidification of endosomal compartments by the H+-V-ATPase to reach low lysosomal pH. Disruption of the correct pH impairs lysosomal function and the balance of protein synthesis and degradation (proteostasis). Mulligan et al. 2024 treated mammalian cells with the small dipeptide LLOMe, which is known to permeabilize lysosomal membranes, and found that LLOMe also impacts late endosomes (LEs) by neutralizing their pH without causing membrane permeabilization. They showed that LLOMe leads to hyperactivation of Rab7, and disruption of tubulation and mannose-6-phosphate receptor (CI-M6PR; also known as IGF2R) recycling on pH-neutralized LEs. pH neutralization (NH4Cl) and expression of Rab7 hyperactive mutants alone can both phenocopy the alterations in tubulation and CI-M6PR trafficking. Mechanistically, pH neutralization increases the assembly of the V1G1 subunit (encoded by ATP6V1G1) of the V-ATPase on endosomal membranes, which stabilizes GTP-bound Rab7 via RILP, a known interactor of Rab7 and V1G1. The authors proposed a novel pathway by which V-ATPase and RILP modulate LE pH and Rab7 activation in concert.

References associated with 1.D.279 family:

Mulligan, R.J., M.M. Magaj, L. Digilio, S. Redemann, C.C. Yap, and B. Winckler. (2024). Collapse of late endosomal pH elicits a rapid Rab7 response via the V-ATPase and RILP. J Cell Sci 137:. 38578235