Cell-type-specific proteostasis networks differ across developing human organs

Abstract Tremendous progress has been made in understanding how proteostasis networks (PNs)—chaperones, co-chaperones, the degradation machinery and associated factors—are regulated cell-autonomously to safeguard cell-type-specific proteomes. However, the extent to which the principles derived from single-cell studies operate within developing tissues, where organ-level cues and multicellular organization shape cellular behaviour, remains unresolved. To address this, we analysed the regulation of PN gene expression during human prenatal development by generating PN-centric maps from single-cell RNA-sequencing datasets of developing limb, skin and skeletal tissues from the Human Cell Atlas. Across tissues, PN expression generally aligned with the functional demands placed on major cell populations. However, transcriptionally similar cell types displayed distinct PN profiles depending on their organ context, indicating that PN composition is not solely dictated by cell identity. Moreover, we uncovered a hierarchy of regulatory control governing PN deployment. In the developing limb—where morphogenetic gradients strongly shape developmental trajectories—PN expression tracked developmental stage rather than differentiation state. By contrast, during skin and skeletal development, PN expression more closely reflected cell-type-specific functional programmes. Together, these findings reinforce the model that the PN is a dynamically deployed system governed by layered regulatory logic, rather than a fixed attribute of cell identity. This article is part of the Theo Murphy meeting issue ‘ProteostaSys: a systems view of proteostasis’.