VPS37 Activators

VPS37 activators encompass a set of compounds that indirectly modulate the activity of the VPS37 protein, a crucial component of the endosomal sorting complex required for transport (ESCRT). These compounds generally exert their influence by perturbing cellular ubiquitin-proteasome systems or endosomal-lysosomal trafficking pathways, leading to enhanced utilization of the ESCRT machinery. For instance, proteasome inhibitors such as MG132, Epoxomicin, and Z-Leu-Leu-Leu-al, increase the cellular pool of ubiquitinated proteins, which may saturate the degradation capacity of the proteasome and shift the burden to the lysosomal pathway, indirectly necessitating enhanced ESCRT function and therefore potentially increasing VPS37 activity. The elevation in ubiquitinated substrates can thus lead to a compensatory upregulation of the ESCRT complex, including VPS37, to facilitate the trafficking of these proteins to lysosomes for degradation.

Additionally, compounds that disrupt endosomal-lysosomal acidification or trafficking, such as Chloroquine and NH4Cl, could create a cellular environment that demands augmented ESCRT activity. These disruptions can result in a feedback mechanism where the cell heightens the efficiency of the ESCRT pathway to cope with the altered endosomal cargo sorting and trafficking, consequently potentiating the activity of VPS37. Similarly, alterations in lipid trafficking induced by compounds like U18666A, and the modulation of clathrin-mediated endocytosis by agents like Pitstop 2, can cause cellular compensatory responses that promote the functional engagement of VPS37.