SRP310108 PRJNA713318 Sensing of intracellular Hcp Levels controls T6SS expression in Vibrio cholerae T6SS secretion is a costly process as each secretion event ejects hundreds of inner tube Hcp molecules as carriers with no other functions. In comparison to bacteria whose T6SSs are tightly regulated, bacteria with constitutive T6SS activity seem inefficient in responding to changing conditions. Here we have discovered a quantity-sensing feedback control that avoids wasteful accumulation of secreted proteins in several T6SS-active pathogens. Intracellular accumulation of T6SS secreted substrates may result from not only deleterious mutations but also impaired recycling of T6SS structural components in low energy environments as it is an ATP-dependent process and crucial for T6SS activity. This quantity-sensing regulation is likely an energy-conserving strategy generally applicable under a variety of stress conditions.