bims-hypusi 2024-05-05 papers

Issue of 2024–05–05
two papers selected by
Sebastian J. Hofer, University of Graz

Exp Mol Med. 2024 May 01.

Glutamine-derived aspartate is required for eIF5A hypusination-mediated translation of HIF-1α to induce the polarization of tumor-associated macrophages.

Dong-Ho Kim, Yoo Na Kang, Jonghwa Jin, Mihyang Park, Daehoon Kim, Ghilsuk Yoon, Jae Won Yun, Jaebon Lee, Soo Young Park, Yu Rim Lee, Jun-Kyu Byun, Yeon-Kyung Choi, Keun-Gyu Park.

Tumor-associated macrophages (TAMs) are vital contributors to the growth, metastasis, and therapeutic resistance of various cancers, including hepatocellular carcinoma (HCC). However, the exact phenotype of TAMs and the mechanisms underlying their modulation for therapeutic purposes have not been determined. Here, we present compelling evidence that glutamine-derived aspartate in TAMs stimulates spermidine production through the polyamine synthesis pathway, thereby increasing the translation efficiency of HIF-1α via eIF5A hypusination. Consequently, augmented translation of HIF-1α drives TAMs to undergo an increase glycolysis and acquire a metabolic phenotype distinct from that of M2 macrophages. Finally, eIF5A levels in tumor stromal lesions were greater than those in nontumor stromal lesions. Additionally, a higher degree of tumor stromal eIF5A hypusination was significantly associated with a more advanced tumor stage. Taken together, these data highlight the potential of inhibiting hypusinated eIF5A by targeting glutamine metabolism in TAMs, thereby opening a promising avenue for the development of novel therapeutic approaches for HCC.

DOI: https://doi.org/10.1038/s12276-024-01214-1

Front Mol Biosci. 2024 ;11 1395220

Implication of Stm1 in the protection of eIF5A, eEF2 and tRNA through dormant ribosomes.

Mengtan Du, Xin Li, Wanlin Dong, Fuxing Zeng.

Background: Dormant ribosomes are typically associated with preservation factors to protect themselves from degradation under stress conditions. Stm1/SERBP1 is one such protein that anchors the 40S and 60S subunits together. Several proteins and tRNAs bind to this complex as well, yet the molecular mechanisms remain unclear. Methods: Here, we reported the cryo-EM structures of five newly identified Stm1/SERBP1-bound ribosomes. Results: These structures highlighted that eIF5A, eEF2, and tRNA might bind to dormant ribosomes under stress to avoid their own degradation, thus facilitating protein synthesis upon the restoration of growth conditions. In addition, Ribo-seq data analysis reflected the upregulation of nutrient, metabolism, and external-stimulus-related pathways in the ∆stm1 strain, suggesting possible regulatory roles of Stm1. Discussion: The knowledge generated from the present work will facilitate in better understanding the molecular mechanism of dormant ribosomes.

Keywords: SERBP1; cryo-EM; dormant ribosome; eEF2; stm1

DOI: https://doi.org/10.3389/fmolb.2024.1395220