bims-hypusi 2023-02-05 papers

Issue of 2023–02–05
three papers selected by
Sebastian J. Hofer, University of Graz

Blood. 2023 Feb 03. pii: blood.2022017584. [Epub ahead of print]

Arginine metabolism regulates human erythroid differentiation through hypusination of eIF5A.

Metabolic programs contribute to hematopoietic stem and progenitor cell (HSPC) fate, but it is not known whether the metabolic regulation of protein synthesis controls HSPC differentiation. Here, we show that SLC7A1/CAT1-dependent arginine uptake and its catabolism to the polyamine spermidine control human erythroid specification of HSPCs via activation of the eukaryotic translation initiation factor 5A (eIF5A). eIF5A activity is dependent on its hypusination, a post-translational modification resulting from the conjugation of the aminobutyl moiety of spermidine to lysine. Notably, attenuation of hypusine synthesis in erythroid progenitors--by inhibition of deoxyhypusine synthase--abrogates erythropoiesis but not myeloid cell differentiation. Proteomic profiling reveals mitochondrial translation to be a critical target of hypusinated eIF5A and accordingly, progenitors with decreased hypusine activity exhibit diminished oxidative phosphorylation. This impacted pathway is critical for eIF5A-regulated erythropoiesis as interventions augmenting mitochondrial function partially rescue human erythropoiesis under conditions of attenuated hypusination. Levels of mitochondrial ribosomal proteins were especially sensitive to the loss of hypusine and we find that the ineffective erythropoiesis linked to haploinsufficiency of RPS14 in del(5q) myelodysplastic syndrome is associated with a diminished pool of hypusinated eIF5A. Moreover, patients with RPL11-haploinsufficient Diamond-Blackfan anemia as well as CD34+ progenitors with downregulated RPL11 exhibit a markedly decreased hypusination in erythroid progenitors, concomitant with a loss of mitochondrial metabolism. Thus, eIF5A-dependent protein synthesis regulates human erythropoiesis and our data reveal a novel role for RPs in controlling eIF5A hypusination in HSPC, synchronizing mitochondrial metabolism with erythroid differentiation.

DOI: https://doi.org/10.1182/blood.2022017584

J Integr Neurosci. 2023 Jan 11. 22(1): 14

The Role of eIF5A1 in LPS-Induced Neuronal Remodeling of the Nucleus Accumbens in the Depression.

Qiang Lyu, Hecun Zou, Li Luo, Wei Liu, Xiang He, Fei-Fei Shang.

BACKGROUND: The pathogenesis of depression is complex, with the brain's reward system likely to play an important role. The nucleus accumbens (NAc) is a key region in the brain that integrates reward signals. Lipopolysaccharides (LPS) can induce depressive-like behaviors and enhance neuroplasticity in NAc, but the underlying mechanism is still unknown. We previously found that eukaryotic translation initiation factor A1 (eIF5A1) acts as a ribosome-binding protein to regulate protein translation and to promote neuroplasticity.
METHODS: In the present study, LPS was administered intraperitoneally to rats and the expression and cellular location of eIF5A1 was then investigated by RT-PCR, Western blotting and immunofluorescence. Subsequently, a neuron-specific lentivirus was used to regulate eIF5A1 expression in vivo and in vitro. Neuroplasticity was then examined by Golgi staining and by measurement of neuronal processes. Finally, proteomic analysis was used to identify proteins regulated by eIF5A1.
RESULTS: The results showed that eIF5A1 expression was significantly increased in the NAc neurons of LPS rats. Following the knockdown of eIF5A1 in NAc neurons, the LPS-induced increases in neuronal arbors and spine density were significantly attenuated. Depression-like behaviors were also reduced. Neurite outgrowth of NAc neurons in vitro also increased or decreased in parallel with the increase or decrease in eIF5A1 expression, respectively. The proteomic results showed that eIF5A1 regulates the expression of many neuroplasticity-related proteins in neurons.
CONCLUSIONS: These results confirm that eIF5A1 is involved in LPS-induced depression-like behavior by increasing neuroplasticity in the NAc. Our study also suggests the brain's reward system may play an important role in the pathogenesis of depression.

Keywords: depression; eukaryotic translation initiation factor A1 (eIF5A1); nucleus accumbens

DOI: https://doi.org/10.31083/j.jin2201014

Life Sci Alliance. 2023 Apr;pii: e202201715. [Epub ahead of print]6(4):

A genome-wide CRISPR functional survey of the human phagocytosis molecular machinery.

Patrick Essletzbichler, Vitaly Sedlyarov, Fabian Frommelt, Didier Soulat, Leonhard X Heinz, Adrijana Stefanovic, Benedikt Neumayer, Giulio Superti-Furga.

Phagocytosis, the process by which cells engulf large particles, plays a vital role in driving tissue clearance and host defense. Its dysregulation is connected to autoimmunity, toxic accumulation of proteins, and increased risks for infections. Despite its importance, we lack full understanding of all molecular components involved in the process. To create a functional map in human cells, we performed a genome-wide CRISPRko FACS screen that identified 716 genes. Mapping those hits to a comprehensive protein-protein interaction network annotated for functional cellular processes allowed retrieval of protein complexes identified multiple times and detection of missing phagocytosis regulators. In addition to known components, such as the Arp2/3 complex, the vacuolar-ATPase-Rag machinery, and the Wave-2 complex, we identified and validated new phagocytosis-relevant functions, including the oligosaccharyltransferase complex (MAGT1/SLC58A1, DDOST, STT3B, and RPN2) and the hypusine pathway (eIF5A, DHPS, and DOHH). Overall, our phagocytosis network comprises elements of cargo uptake, shuffling, and biotransformation through the cell, providing a resource for the identification of potential novel drivers for diseases of the endo-lysosomal system. Our approach of integrating protein-protein interaction offers a broadly applicable way to functionally interpret genome-wide screens.

DOI: https://doi.org/10.26508/lsa.202201715