Differential Metabolic Requirement Governed by Transcription Factor c-Maf Dictates Innate γδT17 Effector Functionality in Mice and Humans
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE193766 | GEO | 2022/04/08
REPOSITORIES: GEO
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Project description:Cellular metabolism has been proposed to govern distinct γδ T cell effector functions, but the underlying molecular mechanisms remain unclear. We show that interleukin-17 (IL-17)-producing γδ T (γδT17) and interferon-γ (IFN-γ)-producing γδ T (γδT1) cells have differential metabolic requirements and that the rate-limiting enzyme isocitrate dehydrogenase 2 (IDH2) acts as a metabolic checkpoint for their effector functions. Intriguingly, the transcription factor c-Maf regulates γδT17 effector function through direct regulation of IDH2 promoter activity. Moreover, mTORC2 affects the expression of c-Maf and IDH2 and subsequent IL-17 production in γδ T cells. Deletion of c-Maf in γδ T cells reduces metastatic lung cancer development, suggesting c-Maf as a potential target for cancer immune therapy. We show that c-Maf also controls IL-17 production in human γδ T cells from peripheral blood and in oral cancers. These results demonstrate a critical role of the transcription factor c-Maf in regulating γδT17 effector function through IDH2-mediated metabolic reprogramming.
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Project description:Differential Metabolic Requirement Governed by Transcription Factor c-Maf Dictates Innate γδT17 Effector Functionality in Mice and Humans
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Project description:Calcium homeostasis is critical for cell proliferation, and emerging evidence shows that cancer cells exhibit altered calcium signals to fulfill their need for proliferation. However, it remains unclear whether there are oncogene-specific calcium homeostasis regulations that can expose novel therapeutic targets. Here, from RNAi screen, we report that adenosylhomocysteinase like protein 1 (AHCYL1), a suppressor of the endoplasmic reticulum (ER) calcium channel protein inositol trisphosphate receptor (IP3R), is selectively upregulated and critical for cell proliferation and tumor growth potential of human NRAS-mutated melanoma, but not for melanoma expressing BRAF V600E. Mechanistically, AHCYL1 deficiency results in decreased ER calcium levels, activates the unfolded protein response (UPR), and triggers downstream apoptosis. In addition, we show that AHCYL1 transcription is regulated by activating transcription factor 2 (ATF2) in NRAS-mutated melanoma. Our work provides evidence for oncogene-specific calcium regulations and suggests AHCYL1 as a novel therapeutic target for RAS mutant-expressing human cancers, including melanoma.
2024-01-15 | GSE253246 | GEO
Project description:Calcium homeostasis is critical for cell proliferation, and emerging evidence shows that cancer cells exhibit altered calcium signals to fulfill their need for proliferation. However, it remains unclear whether there are oncogene-specific calcium homeostasis regulations that can expose novel therapeutic targets. Here, from RNAi screen, we report that adenosylhomocysteinase like protein 1 (AHCYL1), a suppressor of the endoplasmic reticulum (ER) calcium channel protein inositol trisphosphate receptor (IP3R), is selectively upregulated and critical for cell proliferation and tumor growth potential of human NRAS-mutated melanoma, but not for melanoma expressing BRAF V600E. Mechanistically, AHCYL1 deficiency results in decreased ER calcium levels, activates the unfolded protein response (UPR), and triggers downstream apoptosis. In addition, we show that AHCYL1 transcription is regulated by activating transcription factor 2 (ATF2) in NRAS-mutated melanoma. Our work provides evidence for oncogene-specific calcium regulations and suggests AHCYL1 as a novel therapeutic target for RAS mutant-expressing human cancers, including melanoma.ImplicationsOur findings suggest that targeting the AHCYL1-IP3R axis presents a novel therapeutic approach for NRAS-mutated melanomas, with potential applicability to all cancers harboring RAS mutations, such as KRAS-mutated human colorectal cancers.
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Project description:We generated γδT17 cells from splenocytes and compared gene expression profiles of initial and induced γδT17 cells using RNA-seq to explore their biological functions.
2021-01-06 | GSE164262 | GEO
Project description:γδ T cells represent the primary innate source of IL-17 (γδT17) and are known to play a critical role in autoimmune and inflammatory diseases such as psoriasis. We here reported that psoriatic condition (IL-1b and IL-23) reshaped γδT17 cell metabolic signatures and promoted cytokine expression levels compared to homeostatic condition (IL-7). Acetyl-CoA carboxylase 1 (ACC1), a rate-limiting enzyme of fatty acid synthesis (FAS), directs the fate of IL-17-producing CD4 T cells (Th17) differentiation. However, little is known about the role of ACC1-mediated FAS in their innate IL-17-producer counterpart, γδT17 cells. We further investigated the role of FAS in γδT17 by comparing the effect of pharmacological inhibitor Soraphen A (SorA) on DMSO vehicle under psoriatic conditions (IL-1b and IL-23). Interestingly, ACC inhibition shifts the lipid metabolism in γδT17 cells, which allows them to cope with lipid demand without affecting cellular viability.
2025-02-20 | GSE256512 | GEO
Project description:Mobile elements comprise close to one half of the mass of the human genome. Only LINE-1 (L1), an autonomous non-Long Terminal Repeat (LTR) retrotransposon, and its non-autonomous partners-such as the retropseudogenes, SVA, and the SINE, Alu-are currently active human retroelements. Experimental evidence shows that Alu retrotransposition depends on L1 ORF2 protein, which has led to the presumption that LINEs and SINEs share the same basic insertional mechanism. Our data demonstrate clear differences in the time required to generate insertions between marked Alu and L1 elements. In our tissue culture system, the process of L1 insertion requires close to 48 hours. In contrast to the RNA pol II-driven L1, we find that pol III transcribed elements (Alu, the rodent SINE B2, and the 7SL, U6 and hY sequences) can generate inserts within 24 hours or less. Our analyses demonstrate that the observed retrotransposition timing does not dictate insertion rate and is independent of the type of reporter cassette utilized. The additional time requirement by L1 cannot be directly attributed to differences in transcription, transcript length, splicing processes, ORF2 protein production, or the ability of functional ORF2p to reach the nucleus. However, the insertion rate of a marked Alu transcript drastically drops when driven by an RNA pol II promoter (CMV) and the retrotransposition timing parallels that of L1. Furthermore, the "pol II Alu transcript" behaves like the processed pseudogenes in our retrotransposition assay, requiring supplementation with L1 ORF1p in addition to ORF2p. We postulate that the observed differences in retrotransposition kinetics of these elements are dictated by the type of RNA polymerase generating the transcript. We present a model that highlights the critical differences of LINE and SINE transcripts that likely define their retrotransposition timing.
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Project description:Natural IL-17-producing γδ T cells (γδT17 cells) are unconventional innate-like T cells that undergo functional programming in the fetal thymus. However, the intrinsic metabolic mechanisms of γδT17 cell development remain undefined. Here, we demonstrate that mTORC2, not mTORC1, selectively controls the functional fate commitment of γδT17 cells through regulating transcription factor c-Maf expression. scRNA-seq data suggest that fetal and adult γδT17 cells predominately utilize mitochondrial metabolism. mTORC2 deficiency results in impaired Drp1-mediated mitochondrial fission and mitochondrial dysfunction characterized by mitochondrial membrane potential (ΔΨm) loss, reduced oxidative phosphorylation (OXPHOS), and subsequent ATP depletion. Treatment with the Drp1 inhibitor Mdivi-1 alleviates imiquimod-induced skin inflammation. Reconstitution of intracellular ATP levels by ATP-encapsulated liposome completely rescues γδT17 defect caused by mTORC2 deficiency, revealing the fundamental role of metabolite ATP in γδT17 development. These results provide an in-depth insight into the intrinsic link between the mitochondrial OXPHOS pathway and γδT17 thymic programming and functional acquisition.
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Project description:Widely employed by Gram-negative pathogens for competition and pathogenesis, the type six protein secretion system (T6SS) can inject toxic effectors into neighboring cells through the penetration of a spear-like structure comprising a long Hcp tube and a VgrG-PAAR spike complex. The cone-shaped PAAR is believed to sharpen the T6SS spear for penetration but it remains unclear why PAAR is required for T6SS functions in some bacteria but dispensable in others. Here, we report the conditional requirement of PAAR for T6SS functions in Aeromonas dhakensis, an emerging human pathogen that may cause severe bacteremia. By deleting the two PAAR paralogs, we show that PAAR is not required for T6SS secretion, bacterial killing, or specific effector delivery in A. dhakensis. By constructing combinatorial PAAR and vgrG deletions, we demonstrate that deletion of individual PAAR moderately reduced T6SS functions but double or triple deletions of PAAR in the vgrG deletion mutants severely impaired T6SS functions. Notably, the auxiliary-cluster-encoded PAAR2 and VgrG3 are less critical than the main-cluster-encoded PAAR1 and VgrG1&2 proteins to T6SS functions. In addition, PAAR1 but not PAAR2 contributes to antieukaryotic virulence in amoeba. Our data suggest that, for a multi-PAAR T6SS, the variable role of PAAR paralogs correlates with the VgrG-spike composition that collectively dictates T6SS assembly. IMPORTANCE Gram-negative bacteria often encode multiple paralogs of the cone-shaped PAAR that sits atop the VgrG-spike and is thought to sharpen the spear-like T6SS puncturing device. However, it is unclear why PAAR is required for the assembly of some but not all T6SSs and why there are multiple PAARs if they are not required. Our data delineate a VgrG-mediated conditional requirement for PAAR and suggest a core-auxiliary relationship among different PAAR-VgrG modules that may have been acquired sequentially by the T6SS during evolution.
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