Heat shock proteins at the crossroads of endosomal trafficking pathways

Abstract Cells respond to a variety of environmental stressors, including oxidative stress, nutrient deprivation, hypoxia and pathogenic invasion, which challenge cellular homeostasis and trigger adaptive responses. One of the first and most conserved effects is the activation of the heat shock response, which induces the transcription of heat shock proteins (HSPs), molecular chaperones involved in protein folding, assembly and turnover. Beyond their canonical role in maintaining proteostasis, HSPs also exert housekeeping functions, including endocytosis, a process essential for molecule internalization, nutrient uptake, receptor recycling, membrane turnover and cell migration. In this review, we explore the emerging roles of chaperone proteins in endocytic trafficking, with a particular focus on HSP90, HSP70 and small HSPs. We also highlight open questions like their attitude to act in cooperation or competition, and their propensity to form dynamics complexes. In addition, we discuss evidence suggesting that the involvement of these chaperones renders the endocytic process sensitive to stress, speculating on the role of HSPs in endocytosis as an integral component of the cellular stress response. Although some of the molecular mechanisms are still unclear, the available data reveal promising and interesting directions for further research. Graphical Abstract Graphical headlights • Heat shock proteins (HSPs) regulate multiple steps of endocytosis, including cargo internalization, recycling, translocation across endosomal membrane and stabilization of core components of endocytic machinery • Some HSPs can act either cooperatively or antagonistically • HSP-membrane interactions and lipid specificity may drive functional specialization in vesicle trafficking • Stress reprograms HSP activity, making endocytosis a stress-regulated process that supports cell survival