Dataset Information

LKB1/STK11-sensing of mitochondrial function controls Th17 cell responses

ABSTRACT: T helper 17 (Th17) cells are a distinct subset of CD4+ T cells necessary for maintaining gut homeostasis and have prominent roles in autoimmunity and inflammation. Th17 cells have unique metabolic features, including a stem cell-like signature and reliance on mitochondrial respiratory chain function and tricarboxylic acid (TCA) cycle to coordinate metabolic and epigenetic remodeling. Dynamic changes in mitochondrial membrane morphology are key to sustain organelle function. However, it remains unclear whether mitochondrial membrane remodeling orchestrates metabolic and differentiation events in Th17 cells. Here we demonstrate that mitochondrial membrane fusion and tight cristae organization are required for Th17 cell function (i.e. cytokine expression). As a genetic model system we employ Th17 specific deletion of optic atrophy 1 (OPA1), a gene that encodes a protein involved in mitochondrial inner membrane fusion and cristae organization. As a result, we find that Th17 cells rely on mitochondrial fusion (due to their low metabolic activity). Here, we carry out DIA-based differential quantitative proteomic analysis of murine wild-type and OPA1 knock-out Th17 cells. Through Ingenuity pathway analysis and together with transcriptional and metabolomic profiling we identify the serine/threonine kinase liver associated kinase B1 (LKB1/STK11) as an essential node coupling mitochondrial function to IL-17A cytokine expression in T cells.

INSTRUMENT(S): Q Exactive Plus

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): T Cell, Th17 Cell

SUBMITTER: Gerhard Mittler

LAB HEAD: Gerhard Mittler

PROVIDER: PXD036162 | Pride | 2022-10-13

REPOSITORIES: Pride

ACCESS DATA

Dataset's files

Source:

			Action	DRS
	DIA_FranB_Th17_KO_S21.raw	Raw
	DIA_FranB_Th17_KO_S22.raw	Raw
	DIA_FranB_Th17_KO_S23.raw	Raw
	DIA_FranB_Th17_WT_S17.raw	Raw
	DIA_FranB_Th17_WT_S18.raw	Raw

Items per page:

1 - 5 of 8

Publications

An LKB1-mitochondria axis controls TH17 effector function.

Baixauli Francesc F Piletic Klara K Puleston Daniel J DJ Villa Matteo M Field Cameron S CS Flachsmann Lea J LJ Quintana Andrea A Rana Nisha N Edwards-Hicks Joy J Matsushita Mai M Stanczak Michal A MA Grzes Katarzyna M KM Kabat Agnieszka M AM Fabri Mario M Caputa George G Kelly Beth B Corrado Mauro M Musa Yaarub Y Duda Katarzyna J KJ Mittler Gerhard G O'Sullivan David D Sesaki Hiromi H Jenuwein Thomas T Buescher Joerg M JM Pearce Edward J EJ Sanin David E DE Pearce Erika L EL

Nature 20220928 7932

CD4+ T cell differentiation requires metabolic reprogramming to fulfil the bioenergetic demands of proliferation and effector function, and enforce specific transcriptional programmes1-3. Mitochondrial membrane dynamics sustains mitochondrial processes4, including respiration and tricarboxylic acid (TCA) cycle metabolism5, but whether mitochondrial membrane remodelling orchestrates CD4+ T cell differentiation remains unclear. Here we show th ...[more]

PMID: 36171294

Similar Datasets

Project description:T helper 17 (Th17) cells are a distinct subset of CD4+ T cells necessary for maintaining gut homeostasis and have prominent roles in autoimmunity and inflammation1. Th17 cells have unique metabolic features, including a stem cell-like signature2,3 and reliance on mitochondrial respiratory chain function and tricarboxylic acid (TCA) cycle to coordinate metabolic and epigenetic remodeling4,5. Dynamic changes in mitochondrial membrane morphology are key to sustain organelle function6. However, it remains unclear whether mitochondrial membrane remodeling orchestrates metabolic and differentiation events in Th17 cells. Here we demonstrate that mitochondrial membrane fusion and tight cristae organization are required for Th17 cell function (i.e. cytokine expression) but dispensable in other T cell subsets. We find that Th17 cells rely on mitochondrial fusion as a result of their low metabolic activity. Thus, lowering metabolic activity in other T cell subsets by nutrient restriction was sufficient to increase reliance on mitochondrial fusion for effector function. Transcriptional, proteomic, and metabolomic profiling identified the serine/threonine kinase liver associated kinase B1 (LKB1) as an essential node coupling mitochondrial function to cytokine expression in T cells. By genetic and metabolomic approaches, we demonstrate that LKB1 regulates IL-17A expression by controlling TCA cycle metabolites and transcriptional remodeling. Th-17 cell-specific deletion of optic atrophy 1 (OPA1), a protein involved in mitochondrial inner membrane fusion and cristae organization, reduced autoimmune pathogenesis in a mouse model of multiple sclerosis, while additional deletion of LKB1 restored disease. Our findings highlight distinct mitochondrial requirements in CD4+ T cells, identify mitochondrial membrane fusion as a major determinant of Th17 responses, and reveal LKB1 as a sensor of mitochondrial integrity that links mitochondrial cues to effector programs in Th17 cells.

Dataset Information

LKB1/STK11-sensing of mitochondrial function controls Th17 cell responses

Dataset's files

Publications

An LKB1-mitochondria axis controls T<sub>H</sub>17 effector function.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets