Biochimica et biophysica acta. Molecular cell research最新文献

In nature, the majority of known RNA-protein interactions are transient. Our recent study has depicted a novel mechanism known as RNAylation, which covalently links proteins and RNAs. This novel modification bridges the realms of RNA and protein modifications. This review specifically explores RNAylation catalyzed by bacteriophage T4 ADP-ribosyltransferase ModB, with a focus on its protein targets and RNA substrates in the context of Escherichia coli-bacteriophage T4 interaction. Additionally, we discuss the biological significance of RNAylation and present perspectives on RNAylation as a versatile bioconjugation strategy for RNAs and proteins.

Colorectal cancer (CRC) presents ongoing challenges due to limited treatment effectiveness and a discouraging prognosis, underscoring the need for ground-breaking therapeutic approaches. This review delves into the pivotal role of E3 ubiquitin ligases and deubiquitinases (DUBs), underscoring their role as crucial regulators for tumor suppression and oncogenesis in CRC. We spotlight the diverse impact of E3 ligases and DUBs on CRC's biological processes and their remarkable versatility. We closely examine their specific influence on vital signaling pathways, particularly Wnt/β-catenin and NF-κB. Understanding these regulatory mechanisms is crucial for unravelling the complexities of CRC progression. Importantly, we explore the untapped potential of E3 ligases and DUBs as novel CRC treatment targets, discussing aspects that may guide more effective therapeutic strategies. In conclusion, our concise review illuminates the E3 ubiquitin ligases and deubiquitinases pivotal role in CRC, offering insights to inspire innovative approaches for transforming the treatment landscape in CRC.

High-grade serous ovarian cancer (HGSOC) is the most aggressive type of ovarian cancer that causes great threats to women's health. Therefore, we performed RNA-sequencing technology in clinical samples to explore the molecular mechanisms underlying the progression of HGSOC. We then noticed BBOX1, a kind of 2-oxoglutarate-dependent enzyme that is highly expressed in HGSOC tumor tissues. Functional studies showed that BBOX1 promotes cell survival and growth of HGSOC cells in vitro and in vivo. Overexpression of the wild-type BBOX1 promoted cell proliferation, but the Asn191 and Asn292 mutation (key amino acid for the enzymatic activity of BBOX1) counteracted this effect (P < 0.05), which indicated that the promotion effect of BBOX1 on HGSOC cell proliferation was related to its catalytic activity. Downregulation of BBOX1 reduced the activity of the mTORC1 pathway, and decreased protein expression of IP3R3 and phosphorylation level of S6K^Thr389. Metabolomics analysis revealed that BBOX1 is implicated in the glucose metabolism, amino acid metabolism, and nucleotide metabolism of HGSOC cells. In addition, inhibition of BBOX1 suppressed HGSOC cell glycolysis and decreased glucose consumption, lactate production, and the expression of key factors in glycolysis. Finally, we found hypoxia induced the expression of BBOX1 in HGSOC cells and confirmed that BBOX1 could be transcriptionally activated by hypoxia-inducible factor-1α, which could directly bind to the BBOX1 promoter. In summary, BBOX1 mediated the metabolic reprogramming driven by hypoxia, and affected cell metabolism through the mTORC1 pathway, thus acting as an oncogene during HGSOC development.

The nucleotide oligomerization domain (NOD)-like receptors containing pyrin (NLRP) family of cytosolic pattern-recognition receptors play an integral role in host defense following exposure to a diverse set of pathogenic and sterile threats. The canonical event following ligand recognition is the formation of a heterooligomeric signaling complex termed the inflammasome that produces pro-inflammatory cytokines. Dysregulation of this process is associated with many autoimmune, cardiovascular, metabolic, and neurodegenerative diseases. Despite the range of activating stimuli which affect varied cell types, recent literature makes evident that reactive oxygen species (ROS) are integral to the initiation and propagation of inflammasome signaling. Notably, ROS production and inflammasome activation act in a positive feedback loop to promote this potent immune response. While NLRP3 is by far the most extensively studied NLRP, there is also sufficient literature to make these conclusions for other NLRPs family members. In all cases, a knowledge gap exists regarding the molecular targets and effects of ROS. Future research to define these targets and to parse the order and timing of ROS-mediated NLRP activation will provide meaningful insights into inflammasome biology. This will create novel therapeutic opportunities for the numerous illnesses that are impacted by inflammasome activity.

Proteostasis, including protein folding mediated by molecular chaperones, protein degradation, and stress response pathways in organelles like ER (unfolded protein response: UPR), are responsible for cellular protein quality control. This is essential for cell survival as it regulates and reprograms cellular processes. Here, we underscore the role of the proteostasis pathway in Apicomplexan parasites with respect to their well-characterized roles as well as potential roles in many parasite functions, including survival, multiplication, persistence, and emerging drug resistance. In addition to the diverse physiological importance of proteostasis in Apicomplexa, we assess the potential of the pathway's components as chemotherapeutic targets.

Metabolic responses to cellular stress are pivotal in cell ferroptosis, with mitophagy serving as a crucial mechanism in both metabolic processes and ferroptosis. This study aims to elucidate the effects of high glucose on cardiomyocytes (CMs) and cardiac fibroblasts (CFs) regarding ferroptosis and to uncover the underlying mechanisms involved. We examined alterations in glycolysis, mitochondrial oxidative phosphorylation (OXPHOS), and mitophagy, which are essential for metabolic adaptations and ferroptosis. High glucose exposure induced ferroptosis specifically in CMs, while CFs exhibited resistance to ferroptosis, increased glycolytic activity, and no change in OXPHOS. Moreover, high glucose treatment enhanced mitophagy and upregulated mitochondrial ferritin (FTMT). Notably, the combination of FTMT and the autophagy-related protein nuclear receptor coactivator 4 (NCOA4) increased under high glucose conditions. Silencing FTMT significantly impeded mitophagy and eliminated ferroptosis resistance in CFs cultured under high glucose conditions. The transcription factor forkhead box A1 (FOXA1) was upregulated in CFs upon high glucose exposure, playing a crucial role in the increased expression of FTMT. Within the 5′-flanking sequence of the FTMT mRNA, approximately −500 nt from the transcription initiation site, three putative FOXA1 binding sites were identified. High glucose augmented the binding affinity between FOXA1 and these sequences, thereby promoting FTMT transcription. In summary, high glucose upregulated FOXA1 expression and stimulated FTMT promoter activity in CFs, thereby promoting FTMT-dependent mitophagy and conferring ferroptosis resistance in CFs.

Bone marrow-mesenchymal stromal cells (BM-MSCs) are key components of the BM niche, where they regulate hematopoietic stem progenitor cell (HSPC) homeostasis by direct contact and secreting soluble factors. BM-MSCs also protect the BM niche from excessive inflammation by releasing anti-inflammatory factors and modulating immune cell activity. Thanks to these properties, BM-MSCs were successfully employed in pre-clinical HSPC transplantation models, increasing the rate of HSPC engraftment, accelerating the hematological reconstitution, and reducing the risk of graft failure. However, their clinical use requires extensive in vitro expansion, potentially altering their biological and functional properties. In this work, we analyzed the transcriptomic profile of human BM-MSCs sorted as CD45⁻, CD105⁺, CD73⁺, and CD90⁺ cells from the BM aspirates of heathy-donors and corresponding ex-vivo expanded BM-MSCs. We found the expression of immune and inflammatory genes downregulated upon cell culture and selected the transcription factor EGR1 to restore the MSC properties. We overexpressed EGR1 in BM-MSCs and performed in vitro tests to study the functional properties of EGR1-overexpressing BM-MSCs. We concluded that EGR1 increased the MSC response to inflammatory stimuli and immune cell control and potentiated the MSC hematopoietic supportive activity in co-culture assay, suggesting that the EGR1-based reprogramming may improve the BM-MSC clinical use.

The role of micropeptide in cardiomyocyte proliferation remains unknown. We found that MPM (micropeptide in mitochondria) was highly expressed in cardiomyocytes. Compared to MPM^+/+ mice, MPM knockout (MPM^−/−) mice exhibited reduction in left ventricular (LV) mass, myocardial thickness and LV fractional shortening. RNA-sequencing analysis in H9c2, a rat cardiomyocyte cell line, identified downregulation of cell cycle-promoting genes as the most significant alteration in MPM-silencing cells. Consistently, gain- and loss-of-function analyses in H9c2 cells revealed that cardiomyocyte proliferation was repressed by silencing MPM but was promoted by overexpressing MPM. Moreover, the cardiomyocytes in the hearts of MPM^−/− mice displayed reduced proliferation rates. Mechanism investigations disclosed that MPM is crucial for AKT activation in cardiomyocytes. We also identified an interaction between MPM and PTPMT1, and found that silencing PTPMT1 attenuated the effect of MPM in activating the AKT pathway, whereas inhibition of the AKT pathway abrogated the role of MPM in promoting cardiomyocyte proliferation. Collectively, these results indicate that MPM may promote cardiomyocyte proliferation and thus heart growth by interacting with PTPMT1 to activate the AKT pathway. Our findings identify the novel function and regulatory network of MPM and highlight the importance of micropeptides in cardiomyocyte proliferation and heart growth.

This integrative review aims to highlight the importance of investigating the functional role of AHCYL1, also known as IRBIT, in cancer cells. It has recently been suggested that AHCYL1 regulates cell survival/death, stemness capacity, and the host adaptive response to the tumor microenvironment. Despite this knowledge, the role of AHCYL1 in cancer is still controversial, probably due to its ability to interact with multiple factors in a tissue-specific manner. Understanding the mechanisms regulating the functional interplay between the tumor and the tumor microenvironment that controls the expression of AHCYL1 could provide a deeper comprehension of the regulation of tumor development. Addressing how AHCYL1 modulates cellular plasticity processes in a tumoral context is potentially relevant to developing translational approaches in cancer biology.

Epithelial ovarian cancer (EOC), a leading cause of gynecological cancer-related morbidity and mortality and the most common type of ovarian cancer (OC), is widely characterized by alterations in the Epidermal Growth Factor (EGF) signaling pathways. The phenomenon of metastasis is largely held accountable for the majority of EOC-associated deaths. Existing literature reports substantiate evidence on the indispensable role of metabolic reprogramming, particularly the phenomenon of the ‘Warburg effect’ or aerobic glycolysis in priming the cancer cells towards Epithelial to Mesenchymal transition (EMT), subsequently facilitating EMT. Considering the diverse roles of growth factor signaling across different stages of oncogenesis, our prime emphasis was laid on unraveling mechanistic details of EGF-induced ‘Warburg effect’ and resultant metastasis in EOC cells. Our study puts forth Ets1, an established oncoprotein and key player in OC progression, as the prime metabolic sensor to EGF-induced cues from the tumor microenvironment (TME). EGF treatment has been found to induce Ets1 expression in OC cells predominantly through the Extracellular Signal-Regulated Kinase1/2 (ERK1/2) pathway activation. This subsequently results in pronounced glycolysis, characterized by an enhanced lactate production through transcriptional up-regulation of key determinant genes of the central carbon metabolism namely, hexokinase 2 (HK2) and monocarboxylate transporter 4 (MCT4). Furthermore, this study reports an unforeseen combinatorial blockage of HK2 and MCT4 as an effective approach to mitigate cellular metastasis in OC. Collectively, our work proposes a novel mechanistic insight into EGF-induced glycolytic bias in OC cells and also sheds light on an effective therapeutic intervention approach exploiting these insights.