RACK1 maintains mouse hematopoietic stem cells by directly binding to and stabilizing LDB1
TL;DR
Single-cell RNA sequencing indicates that adulthood Rack1 deletion in type I interferon-I-responsive cells leads to aberrant lineage-geneset-scores of transcriptional HSCs and the emergence of stressed HSCs, and Mechanistically, RACK1 prevents HSC loss through maintaining the protein level of LDB1.
Abstract
A core complex with transcription factors (TFs) TAL1/TCF3/GATA2 and adaptors LMO2/LDB1 lies at the top of the hematopoietic transcriptional hierarchy. The mechanism(s) underlying the expression of these components remain elusive. Adaptor RACK1 interacts with multiple TFs and modulates their activation and/or stability. However, a role of RACK1 in the transcriptional control of hematopoietic stem cell (HSC) fates hasn’t been disclosed. Here, we report that RACK1 is expressed across various hematopoietic cell types. Adulthood Rack1 deletion in type I interferon- (IFN-I)-responsive cells leads to rapid and profound hematopoietic failure and HSC loss. HSC exhaustion upon adulthood Rack1 deletion results from cell-intrinsic defects with massive apoptosis. Single-cell RNA sequencing indicates that adulthood Rack1 deletion in IFN-I-responsive cells leads to aberrant lineage-geneset-scores of transcriptional HSCs and the emergence of stressed HSCs. Furthermore, prenatal deletion of Rack1 in hematopoietic cells results in reduced and defective HSCs in the fetal liver. Mechanistically, RACK1 prevents HSC loss through maintaining the protein level of LDB1. The direct interaction between RACK1 and LDB1 suppressing its ubiquitination and subsequent degradation, thereby stabilizes LDB1. Therefore, RACK1 maintains adult and fetal mouse HSCs through, at least partially, directly binding to and stabilizing LDB1.