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Science Advances Jun 2023Autophagy and glycolysis are highly conserved biological processes involved in both physiological and pathological cellular programs, but the interplay between these...
Autophagy and glycolysis are highly conserved biological processes involved in both physiological and pathological cellular programs, but the interplay between these processes is poorly understood. Here, we show that the glycolytic enzyme lactate dehydrogenase A (LDHA) is activated upon UNC-51-like kinase 1 (ULK1) activation under nutrient deprivation. Specifically, ULK1 directly interacts with LDHA, phosphorylates serine-196 when nutrients are scarce and promotes lactate production. Lactate connects autophagy and glycolysis through Vps34 lactylation (at lysine-356 and lysine-781), which is mediated by the acyltransferase KAT5/TIP60. Vps34 lactylation enhances the association of Vps34 with Beclin1, Atg14L, and UVRAG, and then increases Vps34 lipid kinase activity. Vps34 lactylation promotes autophagic flux and endolysosomal trafficking. Vps34 lactylation in skeletal muscle during intense exercise maintains muscle cell homeostasis and correlates with cancer progress by inducing cell autophagy. Together, our findings describe autophagy regulation mechanism and then integrate cell autophagy and glycolysis.
Topics: Autophagy-Related Protein-1 Homolog; Autophagy-Related Proteins; Lysine; Class III Phosphatidylinositol 3-Kinases; Lipids
PubMed: 37267363
DOI: 10.1126/sciadv.adg4993 -
Targeting MS4A4A on tumour-associated macrophages restores CD8+ T-cell-mediated antitumour immunity.Gut Nov 2023Checkpoint immunotherapy unleashes T-cell control of tumours but is suppressed by immunosuppressive myeloid cells. The transmembrane protein MS4A4A is selectively highly...
OBJECTIVE
Checkpoint immunotherapy unleashes T-cell control of tumours but is suppressed by immunosuppressive myeloid cells. The transmembrane protein MS4A4A is selectively highly expressed in tumour-associated macrophages (TAMs). Here, we aimed to reveal the role of MS4A4A TAMs in regulating the immune escape of tumour cells and to develop novel therapeutic strategies targeting TAMs to enhance the efficacy of immune checkpoint inhibitor (ICI) in colorectal cancer.
DESIGN
The inhibitory effect of MS4A4A blockade alone or combined with ICI treatment on tumour growth was assessed using murine subcutaneous tumour or orthotopic transplanted models. The effect of MS4A4A blockade on the tumour immune microenvironment was assessed by flow cytometry and mass cytometry. RNA sequencing and western blot analysis were used to further explore the molecular mechanism by which MS4A4A promoted macrophages M2 polarisation.
RESULTS
MS4A4A is selectively expressed by TAMs in different types of tumours, and was associated with adverse clinical outcome in patients with cancer. In vivo inhibition of MS4A4A and anti-MS4A4A monoclonal antibody treatment both curb tumour growth and improve the effect of ICI therapy. MS4A4A blockade treatment reshaped the tumour immune microenvironment, resulting in reducing the infiltration of M2-TAMs and exhausted T cells, and increasing the infiltration of effector CD8 T cells. Anti-MS4A4A plus anti-programmed cell death protein 1 (PD-1) therapy remained effective in large, treatment-resistant tumours and could induce complete regression when further combined with radiotherapy. Mechanistically, MS4A4A promoted M2 polarisation of macrophages by activating PI3K/AKT pathway and JAK/STAT6 pathway.
CONCLUSION
Targeting MS4A4A could enhance the ICI efficacy and represent a new anticancer immunotherapy.
Topics: Humans; Animals; Mice; Tumor-Associated Macrophages; CD8-Positive T-Lymphocytes; Phosphatidylinositol 3-Kinases; Neoplasms; Macrophages; Tumor Microenvironment; Membrane Proteins
PubMed: 37507218
DOI: 10.1136/gutjnl-2022-329147 -
Medicina (Kaunas, Lithuania) Sep 2023Paroxysmal nocturnal hemoglobinuria (PNH) is a nonmalignant clonal hematopoietic disorder characterized by the lack of glycosylphosphatidylinositol-anchored proteins... (Review)
Review
Paroxysmal nocturnal hemoglobinuria (PNH) is a nonmalignant clonal hematopoietic disorder characterized by the lack of glycosylphosphatidylinositol-anchored proteins (GPI-APs) as a consequence of somatic mutations in the phosphatidylinositol glycan anchor biosynthesis class A () gene. Clinical manifestations of PNH are intravascular hemolysis, thrombophilia, and bone marrow failure. Treatment of PNH mainly relies on the use of complement-targeted therapy (C5 inhibitors), with the newest agents being explored against other factors involved in the complement cascade to alleviate unresolved intravascular hemolysis and extravascular hemolysis. This review summarizes the biology and current treatment strategies for PNH with the aim of reaching a general audience with an interest in hematologic disorders.
Topics: Humans; Hemoglobinuria, Paroxysmal; Hemolysis; Complement System Proteins; Thrombophilia; Glycosylphosphatidylinositols; Biology
PubMed: 37763731
DOI: 10.3390/medicina59091612 -
Science (New York, N.Y.) Oct 2023Neurons relay information via specialized presynaptic compartments for neurotransmission. Unlike conventional organelles, the specialized apparatus characterizing the...
Neurons relay information via specialized presynaptic compartments for neurotransmission. Unlike conventional organelles, the specialized apparatus characterizing the neuronal presynapse must form de novo. How the components for presynaptic neurotransmission are transported and assembled is poorly understood. Our results show that the rare late endosomal signaling lipid phosphatidylinositol 3,5-bisphosphate [PI(3,5)P] directs the axonal cotransport of synaptic vesicle and active zone proteins in precursor vesicles in human neurons. Precursor vesicles are distinct from conventional secretory organelles, endosomes, and degradative lysosomes and are transported by coincident detection of PI(3,5)P and active ARL8 via kinesin KIF1A to the presynaptic compartment. Our findings identify a crucial mechanism that mediates the delivery of synaptic vesicle and active zone proteins to developing synapses.
Topics: Humans; Axonal Transport; Kinesins; Neurons; Synaptic Vesicles; Phosphatidylinositol Phosphates
PubMed: 37824668
DOI: 10.1126/science.adg1075 -
Biomedicine & Pharmacotherapy =... Aug 2023Endometriosis (EM) is characterized by the existence of endometrial mucosa outside the uterine cavity, which causesinfertility, persistent aches, and a decline in... (Review)
Review
Endometriosis (EM) is characterized by the existence of endometrial mucosa outside the uterine cavity, which causesinfertility, persistent aches, and a decline in women's quality of life. Both hormone therapies and nonhormone therapies, such as NSAIDs, are ineffective, generic categories of EM drugs. Endometriosis is a benign gynecological condition, yet it shares a number of features with cancer cells, including immune evasion, survival, adhesion, invasion, and angiogenesis. Several endometriosis-related signaling pathways are comprehensively reviewed in this article, including E2, NF-κB, MAPK, ERK, PI3K/Akt/mTOR, YAP, Wnt/β-catenin, Rho/ROCK, TGF-β, VEGF, NO, iron, cytokines and chemokines. To find and develop novel medications for the treatment of EM, it is essential to implicitly determine the molecular pathways that are disordered during EM development. Additionally, research on the shared pathways between EM and tumors can provide hypotheses or suggestions for endometriosis therapeutic targets.
Topics: Female; Humans; Endometriosis; Phosphatidylinositol 3-Kinases; Quality of Life; Signal Transduction; NF-kappa B; Endometrium
PubMed: 37210898
DOI: 10.1016/j.biopha.2023.114909 -
Frontiers in Endocrinology 2023Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among women of reproductive age. Although promising strides have been made in the field of PCOS... (Review)
Review
Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among women of reproductive age. Although promising strides have been made in the field of PCOS over the past decades, the distinct etiologies of this syndrome are not fully elucidated. Prenatal factors, genetic variation, epigenetic mechanisms, unhealthy lifestyles, and environmental toxins all contribute to the development of this intricate and highly heterogeneous metabolic, endocrine, reproductive, and psychological disorder. Moreover, interactions between androgen excess, insulin resistance, disruption to the hypothalamic-pituitary-ovary (HPO) axis, and obesity only make for a more complex picture. In this review, we investigate and summarize the related molecular mechanisms underlying PCOS pathogenesis from the perspective of the level of signaling pathways, including PI3K/Akt, TGF-β/Smads, Wnt/β-catenin, and Hippo/YAP. Additionally, this review provides an overview of prospective therapies, such as exosome therapy, gene therapy, and drugs based on traditional Chinese medicine (TCM) and natural compounds. By targeting these aberrant pathways, these interventions primarily alleviate inflammation, insulin resistance, androgen excess, and ovarian fibrosis, which are typical symptoms of PCOS. Overall, we hope that this paper will pave the way for better understanding and management of PCOS in the future.
Topics: Pregnancy; Female; Humans; Polycystic Ovary Syndrome; Insulin Resistance; Hyperandrogenism; Androgens; Phosphatidylinositol 3-Kinases; Signal Transduction
PubMed: 37929034
DOI: 10.3389/fendo.2023.1191759 -
Cell Research Aug 2023Migrasomes are recently discovered organelles, which are formed on the ends or branch points of retraction fibers at the trailing edge of migrating cells. Previously, we...
Migrasomes are recently discovered organelles, which are formed on the ends or branch points of retraction fibers at the trailing edge of migrating cells. Previously, we showed that recruitment of integrins to the site of migrasome formation is essential for migrasome biogenesis. In this study, we found that prior to migrasome formation, PIP5K1A, a PI4P kinase which converts PI4P into PI(4,5)P, is recruited to migrasome formation sites. The recruitment of PIP5K1A results in generation of PI(4,5)P at the migrasome formation site. Once accumulated, PI(4,5)P recruits Rab35 to the migrasome formation site by interacting with the C-terminal polybasic cluster of Rab35. We further demonstrated that active Rab35 promotes migrasome formation by recruiting and concentrating integrin α5 at migrasome formation sites, which is likely mediated by the interaction between integrin α5 and Rab35. Our study identifies the upstream signaling events orchestrating migrasome biogenesis.
Topics: Phosphatidylinositols; Integrin alpha5; Organelles; Signal Transduction; rab GTP-Binding Proteins; Phosphatidylinositol 4,5-Diphosphate
PubMed: 37142675
DOI: 10.1038/s41422-023-00811-5 -
Nature Communications Oct 2023Exosomes are secreted to the extracellular milieu when multivesicular endosomes (MVEs) dock and fuse with the plasma membrane. However, MVEs are also known to fuse with...
Exosomes are secreted to the extracellular milieu when multivesicular endosomes (MVEs) dock and fuse with the plasma membrane. However, MVEs are also known to fuse with lysosomes for degradation. How MVEs are directed to the plasma membrane for exosome secretion rather than to lysosomes is unclear. Here we report that a conversion of phosphatidylinositol-3-phosphate (PI(3)P) to phosphatidylinositol-4-phosphate (PI(4)P) catalyzed sequentially by Myotubularin 1 (MTM1) and phosphatidylinositol 4-kinase type IIα (PI4KIIα) on the surface of MVEs mediates the recruitment of the exocyst complex. The exocyst then targets the MVEs to the plasma membrane for exosome secretion. We further demonstrate that disrupting PI(4)P generation or exocyst function blocked exosomal secretion of Programmed death-ligand 1 (PD-L1), a key immune checkpoint protein in tumor cells, and led to its accumulation in lysosomes. Together, our study suggests that the PI(3)P to PI(4)P conversion on MVEs and the recruitment of the exocyst direct the exocytic trafficking of MVEs for exosome secretion.
Topics: Exosomes; Endosomes; Phosphatidylinositols; Multivesicular Bodies
PubMed: 37898620
DOI: 10.1038/s41467-023-42661-0 -
The Journal of Clinical Investigation Jul 2023Deciphering the crosstalk between metabolic reprogramming and epigenetic regulation is a promising strategy for cancer therapy. In this study, we discovered that the...
Deciphering the crosstalk between metabolic reprogramming and epigenetic regulation is a promising strategy for cancer therapy. In this study, we discovered that the gluconeogenic enzyme PCK1 fueled the generation of S-adenosylmethionine (SAM) through the serine synthesis pathway. The methyltransferase SUV39H1 catalyzed SAM, which served as a methyl donor to support H3K9me3 modification, leading to the suppression of the oncogene S100A11. Mechanistically, PCK1 deficiency-induced oncogenic activation of S100A11 was due to its interaction with AKT1, which upregulated PI3K/AKT signaling. Intriguingly, the progression of hepatocellular carcinoma (HCC) driven by PCK1 deficiency was suppressed by SAM supplement or S100A11 KO in vivo and in vitro. These findings reveal the availability of the key metabolite SAM as a bridge connecting the gluconeogenic enzyme PCK1 and H3K9 trimethylation in attenuating HCC progression, thus suggesting a potential therapeutic strategy against HCC.
Topics: Humans; Carcinoma, Hepatocellular; S-Adenosylmethionine; Liver Neoplasms; Phosphatidylinositol 3-Kinases; Epigenesis, Genetic; Phosphoenolpyruvate Carboxykinase (GTP); Intracellular Signaling Peptides and Proteins
PubMed: 37166978
DOI: 10.1172/JCI161713 -
Nature Aug 2023Arrestins have pivotal roles in regulating G protein-coupled receptor (GPCR) signalling by desensitizing G protein activation and mediating receptor internalization. It...
Arrestins have pivotal roles in regulating G protein-coupled receptor (GPCR) signalling by desensitizing G protein activation and mediating receptor internalization. It has been proposed that the arrestin binds to the receptor in two different conformations, 'tail' and 'core', which were suggested to govern distinct processes of receptor signalling and trafficking. However, little structural information is available for the tail engagement of the arrestins. Here we report two structures of the glucagon receptor (GCGR) bound to β-arrestin 1 (βarr1) in glucagon-bound and ligand-free states. These structures reveal a receptor tail-engaged binding mode of βarr1 with many unique features, to our knowledge, not previously observed. Helix VIII, instead of the receptor core, has a major role in accommodating βarr1 by forming extensive interactions with the central crest of βarr1. The tail-binding pose is further defined by a close proximity between the βarr1 C-edge and the receptor helical bundle, and stabilized by a phosphoinositide derivative that bridges βarr1 with helices I and VIII of GCGR. Lacking any contact with the arrestin, the receptor core is in an inactive state and loosely binds to glucagon. Further functional studies suggest that the tail conformation of GCGR-βarr governs βarr recruitment at the plasma membrane and endocytosis of GCGR, and provides a molecular basis for the receptor forming a super-complex simultaneously with G protein and βarr to promote sustained signalling within endosomes. These findings extend our knowledge about the arrestin-mediated modulation of GPCR functionalities.
Topics: beta-Arrestin 1; Cell Membrane; Endocytosis; Endosomes; Glucagon; Heterotrimeric GTP-Binding Proteins; Ligands; Phosphatidylinositols; Receptors, Glucagon; Protein Binding
PubMed: 37558880
DOI: 10.1038/s41586-023-06420-x