Vault is a massive ribonucleoprotein complex found across Eukaryota. The major vault protein (MVP) oligomerizes into an ovular cage, which contains several minor vault components (MVCs) and is thought to transport transiently bound ″cargo″ molecules. Vertebrate vaults house a poly (ADP-ribose) polymerase (known as PARP4 in humans), which is the only MVC with known enzymatic activity. Despite being discovered decades ago, the molecular basis for PARP4′s interaction with MVP remains unclear. In this study, we determined the structure of the human vault cage in complex with PARP4 and its enzymatic substrate NAD + . The structures reveal atomic-level details of the protein-binding interface, as well as unexpected NAD + -binding pockets within the interior of the vault cage. In addition, proteomics data show that human vaults purified from wild-type and PARP4-depleted cells interact with distinct subsets of proteins. Our results thereby support a model in which PARP4′s specific incorporation into the vault cage helps to regulate vault[prime];s selection of cargo and its subcellular localization. Further, PARP4′s proximity to MVP′s NAD + -binding sites could support its enzymatic function within the vault. 

Structural Insights into the Roles of PARP4 and NAD+in the Human Vault Cage

Alternative splicing is a crucial regulator in stem cell biology, intricately influencing the functions of various biological macromolecules, particularly pre-mRNAs and the resultant protein isoforms. This regulatory mechanism is vital in determining stem cell pluripotency, differentiation, and proliferation. Alternative splicing's role in allowing single genes to produce multiple protein isoforms facilitates the proteomic diversity that is essential for stem cells' functional complexity. This review delves into the critical impact of alternative splicing on cellular functions, focusing on its interaction with key macromolecules and how this affects cellular behavior. We critically examine how alternative splicing modulates the function and stability of pre-mRNAs, leading to diverse protein expressions that govern stem cell characteristics, including pluripotency, self-renewal, survival, proliferation, differentiation, aging, migration, somatic reprogramming, and genomic stability. Furthermore, the review discusses the therapeutic potential of targeting alternative splicing-related pathways in disease treatment, particularly focusing on the modulation of RNA and protein interactions. We address the challenges and future prospects in this field, underscoring the need for further exploration to unravel the complex interplay between alternative splicing, RNA, proteins, and stem cell behaviors, which is crucial for advancing our understanding and therapeutic approaches in regenerative medicine and disease treatment. 

Alternative pre-mRNA splicing in stem cell function and therapeutic potential: A critical review of current evidence.

DBP Exposure Affects Oocyte Fertilization Via Extracellular Vesicles-Derived miR-116-5p in Ovarian Granulosa Cells Through Downregulating FOXO3a Expression

Advances in hematopoietic stem cells ex vivo expansion associated with bone marrow niche.

Poikiloderma with neutropenia is a genetic disorder characterized by skin abnormalities, nail dystrophy, bone anomalies, and neutropenia. USB1 encodes a phosphodiesterase essential for processing spliceosomal U6 RNA and some microRNAs, regulating their stability. This study describes a heterozygous de novo USB1 variant (p.P44L) identified in a patient with recurrent infections, hypogammaglobulinemia, and low neutrophil counts. Unlike previously reported mutations, p.P44L affects a conserved proline in the N-terminal domain, predicted to be critical for protein interactions and stability. Functional assays revealed that while U6 RNA processing remained intact, the variant altered protein interactions and subcellular localization, reducing nuclear presence and accumulation within nuclear speckles. In vitro, the variant did not prevent neutrophil differentiation but reduced clonal capacity. In zebrafish, it led to reduced neutrophils and pigmentation. These findings expand the spectrum of genetic traits associated with USB1 and suggest that a heterozygous variant affecting the N-terminal domain of USB1 impacts clinical phenotypes and that hypogammaglobulinemia may be associated with USB1 dysfunction. 

A heterozygous USB1 variant linked to immunodeficiency

Aspartyl-tRNA synthetase 2 (Dars2) is involved in the regulation of mitochondrial protein synthesis and tissue-specific mitochondrial unfolded protein response (UPRmt). The role of Dars2 in the self-renewal and differentiation of hematopoietic stem cells (HSCs) is unknown. Here, we show that knockout (KO) of Dars2 significantly impairs the maintenance of hematopoietic stem and progenitor cells (HSPCs) without involving its tRNA synthetase activity. Dars2 KO results in significantly reduced expression of Srsf2/3/6 and impairs multiple events of mRNA alternative splicing (AS). Dars2 directly localizes to Srsf3-labeled spliceosomes in HSPCs and regulates the stability of Srsf3. Dars2-deficient HSPCs exhibit aberrant AS of mTOR and Slc22a17. Dars2 KO greatly suppresses the levels of labile ferrous iron and iron-sulfur cluster-containing proteins, which dampens mitochondrial metabolic activity and DNA damage repair pathways in HSPCs. Our study reveals that Dars2 plays a crucial role in the iron-sulfur metabolism and maintenance of HSPCs by modulating RNA splicing. 

Aspartyl-tRNA synthetase 2 orchestrates iron-sulfur metabolism in hematopoietic stem cells via fine-tuning alternative RNA splicing.

/pdf/h6pd-overexpression-promotes-ex-vivo-expansion-of-human-cord-3ru9ayt8.pdf

H6PD overexpression promotes ex vivo expansion of human cord blood hematopoietic stem cells

Highly Engrafting Cord Blood Hematopoietic Stem Cells are Enriched in CD34+ Cell Population with High Autophagy Activity

https://link.springer.com/content/pdf/10.1007/s12015-022-10352-w.pdf

The Chaperone Protein Cct5 is Essential for Hematopoietic Stem Cell Maintenance

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Aspartyl-tRNA synthetase 2 orchestrates iron-sulfur metabolism in hematopoietic stem cells via fine-tuning alternative RNA splicing.

H6PD overexpression promotes ex vivo expansion of human cord blood hematopoietic stem cells

Highly Engrafting Cord Blood Hematopoietic Stem Cells are Enriched in CD34+ Cell Population with High Autophagy Activity

H6PD overexpression promotes ex vivo expansion of human cord blood hematopoietic stem cells

The Chaperone Protein Cct5 is Essential for Hematopoietic Stem Cell Maintenance