Cellular proteins act as surfactants to control the interfacial behavior and function of biological condensates.

Interfacial tension governs the behaviors and physiological functions of multiple biological condensates during diverse biological processes. Little is known about whether there are cellular surfactant factors that regulate the interfacial tension and functions of biological condensates within physiological environments. TFEB, a master transcription factor that controls expression of autophagic-lysosomal genes, assembles into transcriptional condensates to control the autophagy-lysosome pathway (ALP). Here, we show that interfacial tension modulates the transcriptional activity of TFEB condensates. MLX, MYC, and IPMK act as synergistic surfactants to decrease the interfacial tension and consequent DNA affinity of TFEB condensates. The interfacial tension of TFEB condensates is quantitatively correlated to their DNA affinity and subsequent ALP activity. The interfacial tension and DNA affinity of condensates formed by TAZ-TEAD4 are also regulated by the synergistic surfactant proteins RUNX3 and HOXA4. Our results indicate that the interfacial tension and functions of biological condensates can be controlled by cellular surfactant proteins in human cells.