bims-hypusi 2026-04-12 papers

Issue of 2026–04–12
three papers selected by
Sebastian J. Hofer, Max Delbrück Center

Cell Death Dis. 2026 Apr 08.

ARID1A deficiency-driven reprogramming of polyamine metabolism promotes endometrial cancer malignancy and immune escape.

Han Tao, Xiaojun Wang, Zhiyi Hu, Yiran Li, Mengwen Kong, Yeli Sun, Kun Gao, Xiaoping Wan.

Metabolic reprogramming is crucial in developing endometrial cancer (EC); however, the mechanisms through which tumor suppressors control metabolites that drive cell proliferation and tumor growth remain unclear. ARID1A, an SWI/SNF chromatin remodeling complex subunit, is frequently mutated in endometrium-related malignancies. Here, EC tumors with ARID1A deleted exhibit increased polyamine production, which enhances malignant proliferative capacity while inhibiting the efficacy of functional CD8+ T cells. Mechanistically, ARID1A depletion in tumor cells interrupts the competitive binding of ARID1A to YAP, causing excessive YAP activation and transcriptionally increasing the expression of polyamine metabolic enzymes, thereby enhancing polyamine synthesis. Increased spermidine production from polyamines can directly hypusinate eukaryotic translation initiation factor 5A (eIF5A) at lysine residues, resulting in efficient histone demethylase LSD1 protein translation. Moreover, polyamine accumulation suppresses the recruitment of CD8+ T cells and hampers antitumor immune responses in vivo. Notably, polyamine depletion induced by eflornithine (DFMO) significantly reduces EC cell proliferative capacity and enhances CD8+ T-cell efficacy. Together, these findings highlight the role of ARID1A in regulating polyamine metabolism and suggest that elevated polyamine levels in tumors enhance malignant cellular behaviors and contribute to immune evasion by inhibiting CD8+ T cell-mediated cytotoxic responses. Therefore, targeting polyamine biosynthesis could be an important therapeutic strategy for ARID1A-inactivated EC.

DOI: https://doi.org/10.1038/s41419-026-08722-0

Mol Metab. 2026 Apr 02. pii: S2212-8778(26)00046-3. [Epub ahead of print] 102362

Translating the blueprint of cell fate: eIF5A-mediated translation regulates cellular identity in the pancreas.

Danielle L Overton, Catharina Bp Villaca, Dorian J Dale, Caleb D Rutan, Morgan A Robertson, Craig T Connors, Emily K Anderson-Baucum, Teresa L Mastracci.

Cellular identity is fundamentally determined by the precise regulation of protein synthesis, which governs growth, differentiation, and function. In the pancreas, the balance between exocrine and endocrine cell types is critical for organ function, and the disruption of protein synthesis in these cells can lead to diseases such as exocrine insufficiency and diabetes. The specialized mRNA translation factor eukaryotic initiation factor 5A (eIF5A) has emerged as an essential regulator of on-demand protein synthesis in professional secretory cells. Here, we investigate the role of eIF5A-mediated mRNA translation in lineage specification during pancreas development. Using genetic mouse models, our studies reveal that loss of eIF5A results in a marked reduction of exocrine volume and a paradoxical expansion of the insulin-producing beta cell population. We reveal that these cellular changes are driven by impaired on-demand protein synthesis during the critical stage of pancreatic cell differentiation. Mechanistically, we show that eIF5A deficiency disrupts the synthesis of proteins critical for proper pathway signaling-most notably Notch-that instruct cell fate decisions. As a result, we observe impaired ductal branching and tip formation as well increased Ngn3+ endocrine progenitors within the ducts. These changes in lineage allocations directly contribute to decreased acinar cell and increased beta cell mass. Remarkably, eIF5A-deficient mice maintain elevated beta cell mass and exhibit preserved glucose tolerance despite severe exocrine deficiency. Collectively, our findings establish that eIF5A-mediated mRNA translation regulates critical developmental signaling pathways and reinforces the finding that disruptions in protein synthesis can reprogram cellular identity and drive disease pathogenesis.

DOI: https://doi.org/10.1016/j.molmet.2026.102362

Protein Sci. 2026 May;35(5): e70550

Novel insights into the assembly of the yeast translation initiation multifactor complex: The critical role of eIF5.

Borja Sáez de la Fuente, Laura Villamayor-Belinchón, José Rafael Ciges-Tomas, Marisa López-Redondo, Carolina Espinosa, Elisabetta Boeri Erba, José L Llácer.

The eukaryotic translation initiation is a biological process in which at least a dozen eukaryotic initiation factors (eIFs) are involved. Specifically, eIF3, eIF1, eIF5, and eIF2 as a ternary complex (eIF2-TC) bound to GTP and methionyl initiator tRNA (Met-tRNAi Met). They interact to form a large complex called the multifactor complex (MFC). This complex binds cooperatively to the ribosomal pre-initiation complex (PIC), promoting the loading of the Met-tRNAi Met into the peptidyl (P) site of the 40S ribosomal subunit. While some interactions between eIFs have been described in the context of the PIC, the interactions within the MFC remain poorly understood. Here, we combine biophysical and biochemical approaches, including mass photometry and native mass spectrometry, with structural biology methods such as electron microscopy, to gain deeper insights into the MFC architecture. Our findings provide novel insights into the critical role of eIF5 during MFC assembly. Notably, two copies of eIF5 are involved in the formation of the MFC. We propose that one eIF5 molecule engages eIF2β and eIF2γ, whereas a second eIF5 molecule interacts with eIF1 together with eIF3c.

Keywords: eIF5; eukaryotic initiation factors; multifactor complex; translation initiation

DOI: https://doi.org/10.1002/pro.70550