ABSTRACT
Loss of protein function is a driving force of ageing. We have identified peptidyl-prolyl isomerase A (PPIA or cyclophilin A) as a dominant chaperone in haematopoietic stem and progenitor cells. Depletion of PPIA accelerates stem cell ageing. We found that proteins with intrinsically disordered regions (IDRs) are frequent PPIA substrates. IDRs facilitate interactions with other proteins or nucleic acids and can trigger liquid-liquid phase separation. Over 20% of PPIA substrates are involved in the formation of supramolecular membrane-less organelles. PPIA affects regulators of stress granules (PABPC1), P-bodies (DDX6) and nucleoli (NPM1) to promote phase separation and increase cellular stress resistance. Haematopoietic stem cell ageing is associated with a post-transcriptional decrease in PPIA expression and reduced translation of IDR-rich proteins. Here we link the chaperone PPIA to the synthesis of intrinsically disordered proteins, which indicates that impaired protein interaction networks and macromolecular condensation may be potential determinants of haematopoietic stem cell ageing.
Subject(s)
Intrinsically Disordered Proteins , Intrinsically Disordered Proteins/chemistry , Cyclophilin A/genetics , Cyclophilin A/metabolism , RNA-Binding Proteins , Hematopoietic Stem Cells/metabolismABSTRACT
Chronic inflammation has been implicated in myelodysplastic syndrome (MDS); however, its role in disease progression is unclear. In a new study by Muto et al., MDS stem cells sparked with TRAF6-activated innate immune signaling were found to outcompete normal counterparts only when fueled by environmental inflammatory stimuli. Non-canonical NF-κB signaling is implicated in inflammatory synergy and MDS progression.
