bims-prolim 2025-06-08 papers

bims-prolim

Biomed News

on Protein lipidation, metabolism and cancer

Issue of 2025–06–08
thirteen papers selected by
Bruna Martins Garcia, CABIMER

Succinylation-related molecular activities in cancer: metabolic adaptations, immune landscape, and prognostic significance in colorectal cancer.
Sialylated IgG expressed in triple-negative breast cancer cells promotes cancer progression by promoting glycolysis.
Histone lactylation-driven feedback loop modulates cholesterol-linked immunosuppression in pancreatic cancer.
SETD2 suppresses tumorigenesis in a KRAS G12C -driven lung cancer model and its catalytic activity is regulated by histone acetylation.
Mechanism and application of lactylation in cancers.
Effect of histone deacetylases on pancreatic physiology and pathology: a review.
The emerging role of GlycoRNAs in immune regulation and recognition.
Tumor-associated Schwann cells promote salivary adenoid cystic carcinoma stem-like reprogramming via IGF2/IGF1R induced histone H3 lysine 18 lactylation.
Substrate recognition and allosteric regulation of synaptic vesicle glutamate transporter VGLUT2.
Efflux of N1-acetylspermidine from hepatoma fosters macrophage-mediated immune suppression to dampen immunotherapeutic efficacy.
Claudin-9 (CLDN9) promotes gastric cancer progression by enhancing the glycolysis pathway and facilitating PD-L1 lactylation to suppress CD8+ T cell anti-tumor immunity.
Selenoprotein K Is a Peripheral ER Membrane Protein.
The lactylation-immune regulatory axis: a potential therapeutic target for migraine prevention and treatment.

Front Immunol. 2025 ;16 1571446

Succinylation-related molecular activities in cancer: metabolic adaptations, immune landscape, and prognostic significance in colorectal cancer.

Zhihang Jiang, Xiaoqing Li, Long Hu, Zheng Jiang.

   Background: Succinylation, a key post-translational modification, plays a crucial role in metabolic regulation and tumor progression. However, its influence on the tumor immune microenvironment and its prognostic implications remain unclear. A systematic pan-cancer analysis of succinylation-related molecular activities is needed.
Methods: Bulk transcriptomic, single-cell RNA sequencing, and spatial transcriptomic data across pan-cancer from TCGA, GEO, TISCH, and multiple other databases were analyzed. Succinylation scores were calculated using Gene Set Variation Analysis (GSVA). The interactions between succinylation scores, immune infiltration, tumor microenvironment, tumor mutational burden, and immunotherapy response were assessed. A succinylation-based prognostic model was constructed and validated in colorectal cancer (CRC) cohorts. PCED1A protein expression was evaluated by immunohistochemistry and Western blotting. The function of PCED1A in CRC was investigated through in vitro experiments.
Results: Succinylation scores were significantly altered in multiple tumor types. Higher succinylation scores correlated with mitochondrial oxidative phosphorylation, while lower succinylation scores were linked to immune cell differentiation. Spatial transcriptomic analysis showed a negative correlation between succinylation scores and immune cell activity in tumor-adjacent regions. A prognostic model consisting of 11 succinylation-related genes (ATP6V1C2, CAPS, DAPK1, P4HA1, PCED1A, RASL10B, AGT, EREG, HYAL1, SARAF, and SLC4A4) was developed. High-risk patients exhibited significantly shorter overall survival. PCED1A was upregulated in CRC and positively associated with SIRT5. Overexpression of PCED1A promoted intracellular protein desuccinylation, along with enhanced CRC cell proliferation, migration, and invasion.
Conclusion: Our analysis demonstrates that succinylation-related molecular activities display distinct expression patterns across cancers, which are associated with metabolic regulation, immune modulation, and disease prognosis. The succinylation-based prognostic model provides a novel risk stratification tool for CRC, while PCED1A-dependent succinylation regulation may serve as a potential therapeutic target.

Keywords:  PCED1A; colorectal cancer; prognostic model; succinylation; tumor immune microenvironment

DOI:  https://doi.org/10.3389/fimmu.2025.1571446
Breast Cancer Res. 2025 Jun 02. 27(1): 96

Sialylated IgG expressed in triple-negative breast cancer cells promotes cancer progression by promoting glycolysis.

Chenyang Hu, Shenghua Zhang, Fugang Duan, Xinmei Huang, Jing Huang, Zhu Zhu, Xiaoning Mo, Weiyan Xu, Lina Wu, Zhimin Fan, Xiaoyan Qiu.

   BACKGROUND: Triple-negative breast cancer (TNBC) is among the most aggressive and lethal subtypes of breast cancer. To date, there are no effective targeted treatment targets. Sialylated IgG (SIA-IgG), with unique sialylated modifications for N-glycosylation at site 162 of the heavy chain of IgG, which was found to be expressed in a variety of cancer cells as a novel procancer factor. Here, we aimed to investigate the expression frequency and procancer mechanisms of SIA-IgG in TNBC, and determine whether the SIA-IgG is a key factor that promotes TNBC and a novel target for TNBC therapy.
METHODS: Immunohistochemical staining, immunofluorescence, and TCGA database analysis were performed to analyze the frequency of SIA-IgG expression in TNBC and the correlation between SIA-IgG expression and patient prognosis. Colony formation, transwell, and Matrigel-transwell assays were used to assess the proliferative and invasive abilities of SIA-IgG. Proteomic mass spectrometry and immunoprecipitation were utilized to identify the key procancer mechanisms of SIA-IgG. Oxygen consumption and extracellular acidification assays were used to elucidate the promotion of glucose metabolism and its mechanism in TNBC. Subcutaneous xenograft models were established to examine the antitumour effects of targeting SIA-IgG.
RESULTS: SIA-IgG was frequently detected in TNBC cells and was negatively associated with prognosis. Moreover, exogenously added SIA-IgG significantly enhanced the proliferation, migration and invasion of TNBC cells. Importantly, SIA-IgG significantly promoted TNBC progression by accelerating glycolysis and lactate reuse, which was dependent on its unique N-glycosylation at the Asn162 site. Conversely, the inhibition of SIA-IgG inhibited cancer cell proliferation and invasion by decreasing ATP and lactate production. Knockdown of SIA-IgG, as well as treatment with the anti-SIA-IgG antibody, significantly inhibited TNBC growth in vivo. Mechanistically, SIA-IgG promoted glycolysis and the lactate cycle mainly through the activation of two pathways: the integrin α6β4-FAK-AKT-HIF-1α-MCT4 axis, and the integrin α6β4-CD44-MCT1 axis.
CONCLUSIONS: These findings suggest that SIA-IgG, by enhancing glycolysis and the lactate cycle, induces metabolic reprogramming and thereby promotes the development of TNBC, making it a promising target for targeted therapy in TNBC.

Keywords:  Glycolysis; Metabolic reprogramming; Sialylated IgG / SIA-IgG; Targeted therapy; Triple-negative breast cancer

DOI:  https://doi.org/10.1186/s13058-025-02052-3
Gut. 2025 Jun 04. pii: gutjnl-2024-334361. [Epub ahead of print]

Histone lactylation-driven feedback loop modulates cholesterol-linked immunosuppression in pancreatic cancer.

Jing Yang, Xiaoning Yu, Mingming Xiao, He Xu, Zhen Tan, Yubin Lei, Yanmei Guo, Wei Wang, Jin Xu, Si Shi, Xianjun Yu.

   BACKGROUND: Pancreatic cancer exhibits limited clinical responses to immunotherapy, highlighting the need for new strategies to counteract its immunosuppressive microenvironment. Although metabolic reprogramming and epigenetic changes contribute to malignancy, the impact of lactate-driven histone lactylation on the tumour microenvironment (TME) has not been fully explored.
OBJECTIVE: This study aims to investigate the role of histone lactylation in pancreatic cancer, focusing on its effects on cholesterol metabolism and antitumour immunity.
DESIGNS: Global lactylome profiling was conducted to identify novel epigenetic mechanisms driven by lactate-induced histone lactylation. Mechanisms were investigated via RNA sequencing, CUT&Tag, immunoprecipitation-mass spectrometry and GST-pull down. Mass cytometry by time-of-flight, in vitro co-culture system, orthotopic pancreatic cancer models and flow cytometry were used to explore Acetyl-CoA acetyltransferase (ACAT2) functions. A proteolysis-targeting chimaera (PROTAC) was developed to degrade ACAT2.
RESULTS: Global lactylome profiling revealed that lactate-driven histone lactylation, particularly H3K18la, promotes the transcriptional activation of ACAT2. ACAT2 acetylates mitochondrial carrier homolog 2 (MTCH2), stabilising it and disrupting oxidative phosphorylation, which increases lactate production and fuels a positive feedback loop in pancreatic cancer. This loop facilitates the delivery of cholesterol via small extracellular vesicles (sEVs), polarising tumour-associated macrophages toward an immunosuppressive M2 phenotype. Additionally, the PROTAC targeting ACAT2 enhanced the efficacy of immune checkpoint blockade therapy in vivo.
CONCLUSIONS: Our findings highlight the critical role of the H3K18la/ACAT2/sEV-cholesterol axis in TME reprogramming. Targeting this pathway may improve anti-PD-1 therapy response in pancreatic cancer, providing a novel therapeutic strategy by linking histone lactylation, cholesterol metabolic reprogramming and immune modulation.

Keywords:  GENE TARGETING; IMMUNE RESPONSE; LIPID METABOLISM; MACROPHAGES; PANCREATIC CANCER

DOI:  https://doi.org/10.1136/gutjnl-2024-334361
bioRxiv. 2025 May 18. pii: 2025.05.16.654513. [Epub ahead of print]

SETD2 suppresses tumorigenesis in a KRAS G12C -driven lung cancer model and its catalytic activity is regulated by histone acetylation.

Ricardo J Mack, Natasha M Flores, Geoffrey C Fox, Hanyang Dong, Metehan Cebeci, Simone Hausmann, Tourkian Chasan, Jill M Dowen, Brian D Strahl, Pawel K Mazur, Or Gozani.

Histone H3 trimethylation at lysine 36 (H3K36me3) is a key chromatin modification that regulates fundamental physiologic and pathologic processes. In humans, SETD2 is the only known enzyme that catalyzes H3K36me3 in somatic cells and is implicated in tumor suppression across multiple cancer types. While there is considerable crosstalk between the SETD2-H3K36me3 axis and other epigenetic modifications, much remains to be understood. Here, we show that SETD2 functions as a potent tumor suppressor in a KRAS G12C -driven lung adenocarcinoma (LUAD) mouse model, and that acetylation at H3K27 (H3K27ac) enhances SETD2 in vitro methylation of H3K36 on nucleosome substrates. In vivo , SETD2 ablation accelerates lethality in an autochthonous KRAS G12C -driven LUAD mouse tumor model. Biochemical analyses reveal that polyacetylation of histone tails in a nucleosome context promote H3K36 methylation by SETD2. In addition, monoacetylation exerts position-specific effects to stimulate SETD2 methylation activity. In contrast, mono-ubiquitination at various histone sites, including at H2AK119 and H2BK120, does not affect SETD2 methylation of nucleosomes. Together, these findings provide insight into how SETD2 integrates histone modification signals to regulate H3K36 methylation and highlights the potential role of SETD2-associated epigenetic crosstalk in cancer pathogenesis.

DOI: https://doi.org/10.1101/2025.05.16.654513
Cell Biosci. 2025 Jun 04. 15(1): 76

Mechanism and application of lactylation in cancers.

Jiewen Wang, Mingjing Peng, Linda Oyang, Mengzhou Shen, Shizhen Li, Xianjie Jiang, Zongyao Ren, Qiu Peng, Xuemeng Xu, Shiming Tan, Longzheng Xia, Wenjuan Yang, Haofan Li, Nayiyuan Wu, Yanyan Tang, Jinguan Lin, Qianjin Liao, Yaqian Han, Yujuan Zhou.

  Lactate is a crucial product of cancer metabolism, creating an acidic environment that supports cancer growth and acts as a substrate for lactylation. Lactylation, a newly discovered epigenetic modification, plays a vital role in cancer cell signaling, metabolic reprogramming, immune response, and other functions. This review explores the regulation of lactylation, summarizes recent research on its role in cancers, and highlights its application in cancer drug resistance and immunotherapy. These insights aim to provide new avenues for targeting lactylation in cancer therapy.

Keywords:  Cancer; Cancer resistance; Immunotherapy; Lactylation

DOI:  https://doi.org/10.1186/s13578-025-01415-9
Int J Biol Macromol. 2025 Jun 01. pii: S0141-8130(25)05389-9. [Epub ahead of print]318(Pt 1): 144837

Effect of histone deacetylases on pancreatic physiology and pathology: a review.

Xinran Song, Xiaofeng Wu, Jun Yang, Ran Xue.

  The incidence of pancreatic diseases is increasing worldwide. Thus, there is a need to develop novel therapeutic strategies and identify molecular targets for pancreatic diseases. Histone deacetylases (HDACs), which are involved in epigenetic regulation, mediate diverse physiological functions and regulate various vital activities in the pancreas. This review examines the roles of HDACs in different pancreatic cells and the potential therapeutic value of targeting HDACs in pancreatic diseases. Additionally, the potential of HDAC inhibitors as a combination therapy strategy for pancreatic diseases has been discussed, providing novel insights and directions for the diagnosis, treatment, and prevention of pancreatic diseases.

Keywords:  Cell biology; Histone deacetylases; Insights; Pancreas; Pancreatic cancer

DOI:  https://doi.org/10.1016/j.ijbiomac.2025.144837
Immunol Lett. 2025 May 30. pii: S0165-2478(25)00081-1. [Epub ahead of print]276 107048

The emerging role of GlycoRNAs in immune regulation and recognition.

Nicole Montag, Pavlos Gousis, Jürgen Wittmann.

  Glycosylation, the enzymatic attachment of glycans to biomolecules, is a vital post-translational modification that impacts protein stability, immune recognition, and cellular communication. Traditionally associated with proteins and lipids, recent discoveries have revealed the existence of glycosylated RNAs (glycoRNAs), expanding our understanding of RNA modifications. GlycoRNAs challenge conventional paradigms by suggesting that glycosylation may regulate RNA stability, localization, and interactions with glycan-binding proteins, such as sialic acid-binding immunoglobulin-type lectins (Siglecs) and selectins. These interactions are particularly significant in the immune system, where glycosylation plays a key role in antigen recognition, immune cell trafficking, and pathogen detection. The potential implications of glycoRNAs in immune regulation and disease are profound, with roles in autoimmune disorders, cancer, and infectious diseases. Advances in glycobiology, including mass spectrometry, RNA sequencing, glycan microarrays, and click chemistry technologies, are driving the growth of glycoRNA research and its translational applications. Understanding glycoRNAs could lead to new therapeutic opportunities, including glycoengineering, biomarker discovery, and targeted immune interventions. Despite challenges including low abundance and complex structure, research into glycoRNA is progressing rapidly, revealing their roles in immune responses and disease mechanisms. This review synthesizes the current knowledge on glycoRNAs, highlighting their emerging significance in immunology and outlining future research directions.

Keywords:  Glycan-binding proteins; GlycoRNA; Glycosylation; Immune regulation; Small RNAs

DOI:  https://doi.org/10.1016/j.imlet.2025.107048
Cancer Lett. 2025 Jun 02. pii: S0304-3835(25)00414-8. [Epub ahead of print] 217847

Tumor-associated Schwann cells promote salivary adenoid cystic carcinoma stem-like reprogramming via IGF2/IGF1R induced histone H3 lysine 18 lactylation.

Su Chen, Guangzhao Huang, Zhiyong Guo, Zijian Guo, Chang Cao, Guile Zhao, Grace Paka Lubamba, Yuncong Huang, Jiajin Yang, Haosen Lian, Yufei Hua, Cheng Miao, Jiefei Shen, Ming Xuan, Xiufa Tang, Zhangfan Ding, Chunjie Li.

  Salivary adenoid cystic carcinoma (SACC) is characterized by an exceptionally dense neural network within its tumor microenvironment. Schwann cells (SCs), an essential component of this neural network, have recently emerged as critical mediators of tumor progression. However, SACC-induced SCs reprogramming, as well as the functional significance and molecular mechanisms of tumor-associated Schwann cells (TA-SCs), remains largely elusive. We employed tissue-clearing-based three-dimensional imaging to evaluate the SACC tumor microenvironment with high spatial resolution. We also characterized SCs heterogeneity using single-cell RNA sequencing data from GEO. We investigated the biological phenotypes transformation and revealed the transcriptome characteristics of TA-SCs in SACC, indicating that TGF-β1 exerts its function through c-Jun activation, which is pivotal for driving TA-SCs reprogramming. Furthermore, we determined that TA-SCs enhance SACC cell proliferation, migration, invasion, cisplatin resistance, and stemness. We further discovered that TA-SCs elevate histone lactylation in SACC via paracrine IGF2 signaling. Inhibition of IGF2/IGF1R signaling curbed histone H3 lysine 18 lactylation (H3K18la) in SACC and attenuated the IGF2-driven stem-like reprogramming effect, while simultaneous blockade of TGF-βR1 and IGF1R activation maximally restricted this reprogramming. These findings underscore the pivotal role of TA-SCs in SACC progression and stem-like reprogramming via IGF2/IGF1R-H3K18la axis, representing promising therapeutic targets for this malignancy.

Keywords:  IGF type 1 receptor (IGF1R); Schwann cells; histone modification; perineural invasion; tumor microenvironment

DOI:  https://doi.org/10.1016/j.canlet.2025.217847
Nat Struct Mol Biol. 2025 Jun 03.

Substrate recognition and allosteric regulation of synaptic vesicle glutamate transporter VGLUT2.

Fei Li, Jacob Eriksen, Juan A Oses-Prieto, Yessica K Gomez, Hongfei Xu, Surabhi Hareendranath, Poulomi Das, Janet Finer-Moore, Phuong Nguyen, Alisa Bowen, Andrew Nelson, Alma Burlingame, Michael Grabe, Robert M Stroud, Robert H Edwards.

The concentration of neurotransmitters inside synaptic vesicles (SVs) underlies the quantal nature of synaptic transmission. Uptake of glutamate, the principal excitatory neurotransmitter, is driven by membrane potential. To prevent nonquantal efflux of glutamate after SV exocytosis, the vesicular glutamate transporters (VGLUTs) are allosterically inhibited by the neutral pH of the synaptic cleft. To elucidate the mechanism, we determined high-resolution structures of rat VGLUT2 with a cyclic analog of glutamate. We propose a mechanism of substrate recognition in which a positively charged cytoplasmic vestibule electrostatically attracts the negatively charged substrate. We also identify modification of VGLUT2 by palmitoylation and find that this promotes retrieval of the transporter after exocytosis. The structure also reveals an extensive network of electrostatic interactions that forms the cytoplasmic gate. Functional analysis of a mutant that disrupts the network shows how this cytoplasmic gate confers the allosteric requirement for lumenal H+ required to restrict VGLUT activity to SVs.

DOI: https://doi.org/10.1038/s41594-025-01568-8
Immunity. 2025 May 27. pii: S1074-7613(25)00227-4. [Epub ahead of print]

Efflux of N1-acetylspermidine from hepatoma fosters macrophage-mediated immune suppression to dampen immunotherapeutic efficacy.

Zheng-Yu Liu, Cai-Yuan Wu, Rui-Qi Wu, Jun-Cheng Wang, Chun-Xiang Huang, Xu-Yan Wang, Yaojun Zhang, Limin Zheng, Yun Chen, Xiang-Ming Lao, Dong-Ping Chen, Dong-Ming Kuang.

  Metabolic reprogramming is a hallmark of tumor progression. Here, we examined the metabolic profile of hepatocellular carcinoma (HCC), a disease that responds poorly to immune checkpoint blockade (ICB). Polyamine metabolism increased in HCC samples. Of the polyamine spectrum analyzed, N1-acetylspermidine (N1-Ac-Spd) accumulated in HCC tissue as compared with nontumoral liver tissue and was elevated in paired plasma. Injection of N1-Ac-Spd promoted tumor progression in preclinical models and compromised the efficacy of ICB. Inflammatory macrophages increased expression of the spermidine/spermine N1-acetyltransferase 1, SAT1, in hepatoma cells, leading to increased N1-Ac-Spd efflux via the polyamine transporter protein SLC3A2. Mechanistically, N1-Ac-Spd efflux activated SRC signaling in a charge-dependent manner, which in turn induced CCL1+ macrophage polarization, the recruitment of CCR8+ regulatory T cells, and an immunosuppressive tumor microenvironment (TME). In vivo interventions targeting SLC3A2, SAT1, or CCL1 enhanced the antitumor effects of ICB therapy. Our findings provide insight into the mechanisms whereby metabolic reprogramming fosters an immunosuppressive TME, with implications for the treatment of HCC.

Keywords:  N1-acetylspermidine; hepatocellular carcinoma; immune privilege; immunotherapy; inflammatory macrophages; polyamine metabolism; regulatory T cells

DOI:  https://doi.org/10.1016/j.immuni.2025.05.006
Cancer Pathog Ther. 2025 May;3(3): 253-266

Claudin-9 (CLDN9) promotes gastric cancer progression by enhancing the glycolysis pathway and facilitating PD-L1 lactylation to suppress CD8+ T cell anti-tumor immunity.

Xingbin Hu, Wenhao Ouyang, Haizhu Chen, Zhihong Liu, Zijia Lai, Herui Yao.

   Background: Gastric cancer (GC) is a common malignancy characterized by the absence of reliable prognostic indicators and effective therapeutic targets. Claudin-9 (CLDN9) has been demonstrated to be upregulated in various cancers. However, its prognostic value, biological function, and regulatory mechanisms in GC remain unclear. Therefore, this study aimed to elucidate the role of CLDN9 in GC progression and its underlying mechanisms.
Methods: We utilized consensus cluster, random survival forest, and multivariate Cox regression analyses to identify CLDN9 in GC. Subsequently, we evaluated the mRNA and protein levels of CLDN9 in GC using quantitative real-time polymerase chain reaction (PCR) (qRT-PCR), Western blotting (WB), and immunohistochemistry (IHC). Furthermore, the role of CLDN9 in GC progression was investigated using a series of functional in vivo and in vitro experiments. Finally, we elucidated the molecular mechanisms of CLDN9 using bioinformatics, molecular biology, animal models, and patient tissue specimens.
Results: Two GC subtypes with survival and functional differences were identified based on glycolytic metabolic genes in the Cancer Genome Atlas (TCGA)- Stomach adenocarcinoma (STAD) dataset. A prognostic risk score was calculated using seven genes to assess the overall survival (OS) in GC. Using random survival forest and multivariate Cox analyses, we identified CLDN9 as the key gene linked to the glycolytic subtype and prognosis of GC. CLDN9 expression was significantly upregulated in patients with GC as well as in GC cells. CLDN9 knockdown inhibited tumor proliferation, invasion, and metastasis both in vivo and in vitro. Mechanistically, CLDN9 was found to regulate lactate dehydrogenase A (LDHA) expression and promote glycolytic metabolism by activating the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/hypoxia-inducible factor 1-alpha (HIF1α) signaling pathway. Additionally, lactate, a glycolytic metabolite, enhanced programmed cell death ligand 1 (PD-L1) lactylation and stability, which suppressed anti-tumor immunity in CD8+ T cells, thereby contributing to GC progression.
Conclusions: CLDN9 expression is associated with GC development and progression. Mechanistically, CLDN9 enhances the glycolysis pathway and facilitates PD-L1 lactylation through the PI3K/AKT/HIF1α signaling pathway, thereby suppressing anti-tumor immunity in CD8+ T cells. CLDN9 has the potential to serve as a novel prognostic marker and therapeutic target for GC.

Keywords:  CLDN9; Gastric cancer; Glycolysis; Immune evasion; Lactylation; PD-L1

DOI:  https://doi.org/10.1016/j.cpt.2024.09.006
Biochemistry. 2025 Jun 04.

Selenoprotein K Is a Peripheral ER Membrane Protein.

Atinuke Odunsi, Erfan Rahmani, Farid Ghelichkhani, Brigette Romero, Mona Batish, Sharon Rozovsky.

Selenoprotein K (selenok) is a small, disordered membrane protein associated with the endoplasmic reticulum (ER) that is involved in protein palmitoylation and protein quality control. Through these processes, it influences calcium homeostasis, cellular migration, and phagocytosis. Thus, it is implicated in cancer, neurodegenerative diseases, and autophagy. So far, selenok has been considered a single-pass membrane protein whose N-terminus is in the ER lumen while its C-terminus, which contains the reactive selenocysteine, is in the cytoplasm. Here, we show that selenok is, in fact, a peripheral membrane protein that is anchored to the cytoplasmic side of the ER membrane. We demonstrate, using immunofluorescence microscopy and the substituted cysteine accessibility method in combination with selective membrane permeabilization, that both selenok's N- and C-terminus are in the cytoplasm. Using the same techniques, we demonstrate that, in contrast, selenoprotein S (selenos), a functionally related member of the selenoprotein family, is a transmembrane protein with a cytoplasmic C-terminus and an N-terminus exposed to the ER lumen. The findings that selenok is a peripheral membrane protein and that its N- and C-terminal segments, along with the hydrophilic side of its amphipathic α-helix, are exposed to the cytoplasm, imply that they can interact with cytoplasmic extramembranous regions of ER-residing membrane proteins and soluble protein partners. Selenok is predicted to possess multiple SLiMs (short linear motifs) involved in protein interactions, and its peripheral topology suggests that all these motifs, including those located within the amphipathic α-helix, are exposed and accessible to cytoplasmic-accessible partners.

DOI: https://doi.org/10.1021/acs.biochem.5c00062
J Headache Pain. 2025 Jun 04. 26(1): 134

The lactylation-immune regulatory axis: a potential therapeutic target for migraine prevention and treatment.

Liu Wang, Zhixuan Lan, Ying He, Yue Cheng, Ruilin He, Zongbin Jiang.



Keywords:  Immune mediation; Lactylation; Mendelian randomization; Migraine; Multi-omics; Single-cell RNA sequencing

DOI:  https://doi.org/10.1186/s10194-025-02075-3