The Rac2 GTPase contributes to Cathepsin H-mediated protection against cytokine-induced β-cell apoptosis
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ABSTRACT:
PROVIDER: PRJNA562913 | ENA |
REPOSITORIES: ENA
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Project description:In type 1 diabetes (T1D), the pancreatic β-cells are specifically destroyed by the immune system. In this process, local release of pro-inflammatory cytokines, such as IL-1β and IFNγ, contribute to β-cell apoptosis. Genome-wide association studies have identified more than 60 risk loci for T1D, including chr15q25.1 with the candidate gene CTSH (cathepsin H). We previously showed that T1D-associated risk variants in CTSH affect the expression of CTSH and are associated with disease progression in children with newly diagnosed T1D.We further found that CTSH increases β-cell function and protects against cytokine-induced apoptosis. Using global gene expression analysis, the purpose of the present study was to identify the genes and mechanisms through which CTSH mediates its protective effects. Microarray analysis identified a total of 63 annotated genes differentially expressed between stable CTSH-overexpressing insulin-secreting INS-1 cells and control cells transfected with an empty vector after treatment with IL-1β and IFNγ for 0, 6 and 16 hours. Permutation test taking all time-points into consideration identified 10 genes differentially expressed between the CTSH-overexpressing cells and the control cells: Elmod1, Fam49a, Gas7, Gna15, Msrb3, Nox1, Ptgs1, Rac2, Scn7a and Ttn. Pathway analysis identified one significant pathway “Inflammation mediated by chemokine and cytokine signaling pathway” with the genes Gna15, Ptgs1 and Rac2. Since Gna15 and Rac2 were upregulated by CTSH overexpression, their expression was knocked down using small interfering RNAs (siRNAs) to evaluate their potential as mediators of the protective effect of CTSH. Knockdown of Rac2 abolished the protective effect of CTSH overexpression on cytokine-induced apoptosis.
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Project description:Lysosomal cathepsins regulate an exquisite range of biological functions, and their deregulation is associated with inflammatory, metabolic and degenerative disease in humans. Here, we identified a key cell-intrinsic role for cathepsin B as a negative feedback regulator of lysosomal biogenesis and autophagy. Mice and macrophages lacking cathepsin B activity had increased resistance to the cytosolic bacterial pathogen Francisella novicida. Genetic deletion or pharmacological inhibition of cathepsin B downregulated mTOR activity and prevented cleavage of the lysosomal calcium channel TRPML1. These events drove transcription of lysosomal and autophagy genes via the transcription factor TFEB, which increased lysosomal biogenesis and activation of autophagy-initiation kinase ULK1 for clearance of the bacteria. Our results identified a fundamental biological function of cathepsin B in providing a checkpoint for homeostatic maintenance of lysosome population and basic recycling functions in the cell. We used microarrays to explore the gene expression profiles differentially expressed in bone marrow-derived macrophages (BMDM) isolated from cathepsin B-/- and wild-type mice.
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Project description:Emerging evidence suggests that several of the lysosomal cathepsin proteases are genetically associated with type 1 diabetes (T1D) and participate in immune-mediated destruction of the pancreatic β cells. We previously reported that the T1D candidate gene cathepsin H is downregulated by pro-inflammatory cytokines in human pancreatic islets and regulates β-cell function, apoptosis, and disease progression in children with new-onset T1D. In the present study, the objective was to investigate the expression patterns of all 15 known cathepsins in β-cell model systems and examine their role in the regulation of cytokine-induced apoptosis. Real-time qPCR screening of the cathepsins in human islets, 1.1B4 and INS-1E β-cell models identified several cathepsins that were expressed and regulated by pro-inflammatory cytokines. Using small interfering RNAs to knock down (KD) the cytokine-regulated cathepsins, we identified an anti-apoptotic function of cathepsin C as KD increased cytokine-induced apoptosis. KD of cathepsin C correlated with increased phosphorylation of JNK and p38 mitogen-activated protein kinases, and elevated chemokine CXCL10/IP-10 expression. This study suggests that cathepsin C is a modulator of β-cell survival, and that immune modulation of cathepsin expression in islets may contribute to immune-mediated β-cell destruction in T1D.
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Project description:Lysosomal cathepsins regulate an exquisite range of biological functions, and their deregulation is associated with inflammatory, metabolic and degenerative disease in humans. Here, we identified a key cell-intrinsic role for cathepsin B as a negative feedback regulator of lysosomal biogenesis and autophagy. Mice and macrophages lacking cathepsin B activity had increased resistance to the cytosolic bacterial pathogen Francisella novicida. Genetic deletion or pharmacological inhibition of cathepsin B downregulated mTOR activity and prevented cleavage of the lysosomal calcium channel TRPML1. These events drove transcription of lysosomal and autophagy genes via the transcription factor TFEB, which increased lysosomal biogenesis and activation of autophagy-initiation kinase ULK1 for clearance of the bacteria. Our results identified a fundamental biological function of cathepsin B in providing a checkpoint for homeostatic maintenance of lysosome population and basic recycling functions in the cell.
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