Abstract
Gain of even a single chromosome leads to changes in human cell physiology and uniform perturbations of specific cellular processes, including downregulation of DNA replication pathway, upregulation of autophagy and lysosomal degradation, and constitutive activation of the type I interferon response. Little is known about the molecular mechanisms underlying these changes. We show that the constitutive nuclear localization of TFEB, a transcription factor that activates the expression of autophagy and lysosomal genes, is characteristic of human trisomic cells. Constitutive nuclear localization of TFEB in trisomic cells is independent of mTORC1 signaling, but depends on the cGAS-STING activation. Trisomic cells accumulate cytoplasmic dsDNA, which activates the cGAS-STING signaling cascade, thereby triggering nuclear accumulation of the transcription factor IRF3 and, consequently, upregulation of interferon-stimulated genes. cGAS depletion interferes with TFEB-dependent upregulation of autophagy in model trisomic cells. Importantly, activation of both the innate immune response and autophagy occurs also in primary trisomic embryonic fibroblasts, independent of the identity of the additional chromosome. Our research identifies the cGAS-STING pathway as an upstream regulator responsible for activation of autophagy and inflammatory response in human cells with extra chromosomes, such as in Down syndrome or other aneuploidy-associated pathologies.
Highlights
Gain of even a single chromosome leads to changes in human cell physiology and uniform perturbations of specific cellular processes, including downregulation of DNA replication pathway, upregulation of autophagy and lysosomal degradation, and constitutive activation of the type I interferon response
Detailed examination of the transcriptome and proteome data showed that the targets of the transcription factor TFEB, such as LC3 (MAP1LC3B), SQSTM1, VPS18, and WIPI1, as well as cathepsins D, B and A, and other lysosome-specific proteases were upregulated in the analyzed cell lines (Fig. 1a, b and Supplementary Data 1)
By IF, we observed that loss of cGAS and stimulator of interferon (IFN) genes (STING) significantly reduced the accumulation of nuclear TFEB in trisomic cells, but not in diploid cells (Fig. 5c–f)
Summary
Gain of even a single chromosome leads to changes in human cell physiology and uniform perturbations of specific cellular processes, including downregulation of DNA replication pathway, upregulation of autophagy and lysosomal degradation, and constitutive activation of the type I interferon response. Trisomic cells accumulate cytoplasmic dsDNA, which activates the cGAS-STING signaling cascade, thereby triggering nuclear accumulation of the transcription factor IRF3 and, upregulation of interferon-stimulated genes. Established model mammalian somatic cell lines with defined chromosome gains have allowed in vitro studies of the effects of aneuploidy on cellular function[9,10,11] These studies revealed that the gain of a single chromosome triggers a uniform and conserved deregulation of specific pathways that primarily affect cell proliferation and genome and proteome homeostasis[7,12,13]. Phosphorylated IRF3 and NF-κB translocate to the nucleus, where they trigger transcription of type 1 interferons and other cytokines, which subsequently elicit the expression of interferon-stimulated genes (ISGs)[29] Whether this signaling pathway is activated in constitutive trisomic cells has not yet been tested
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