Amélie Bernard1, Meiyan Jin1, Patricia González-Rodríguez2, Jens Füllgrabe2, Elizabeth Delorme-Axford1, Steven K Backues1, Bertrand Joseph2, Daniel J Klionsky3. 1. Life Sciences Institute, and the Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA. 2. Department of Oncology Pathology, Cancer Centrum Karolinska, Karolinska Institutet, Stockholm 17176, Sweden. 3. Life Sciences Institute, and the Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: klionsky@umich.edu.
Abstract
BACKGROUND: Autophagy is a conserved process mediating vacuolar degradation and recycling. Autophagy is highly upregulated upon various stresses and is essential for cell survival in deleterious conditions. Autophagy defects are associated with severe pathologies, whereas unchecked autophagy activity causes cell death. Therefore, to support proper cellular homeostasis, the induction and amplitude of autophagy activity have to be finely regulated. Transcriptional control is a critical, yet largely unexplored, aspect of autophagy regulation. In particular, little is known about the signaling pathways modulating the expression of autophagy-related genes, and only a few transcriptional regulators have been identified as contributing in the control of this process. RESULTS: We identified Rph1 as a negative regulator of the transcription of several ATG genes and a repressor of autophagy induction. Rph1 is a histone demethylase protein, but it regulates autophagy independently of its demethylase activity. Rim15 mediates the phosphorylation of Rph1 upon nitrogen starvation, which causes an inhibition of its function. Preventing Rph1 phosphorylation or overexpressing the protein causes a severe block in autophagy induction. A similar function of Rph1/KDM4 is seen in mammalian cells, indicating that this process is highly conserved. CONCLUSION: Rph1 maintains autophagy at a low level in nutrient-rich conditions; upon nutrient limitation, the inhibition of its activity is a prerequisite to the induction of ATG gene transcription and autophagy.
BACKGROUND: Autophagy is a conserved process mediating vacuolar degradation and recycling. Autophagy is highly upregulated upon various stresses and is essential for cell survival in deleterious conditions. Autophagy defects are associated with severe pathologies, whereas unchecked autophagy activity causes cell death. Therefore, to support proper cellular homeostasis, the induction and amplitude of autophagy activity have to be finely regulated. Transcriptional control is a critical, yet largely unexplored, aspect of autophagy regulation. In particular, little is known about the signaling pathways modulating the expression of autophagy-related genes, and only a few transcriptional regulators have been identified as contributing in the control of this process. RESULTS: We identified Rph1 as a negative regulator of the transcription of several ATG genes and a repressor of autophagy induction. Rph1 is a histone demethylase protein, but it regulates autophagy independently of its demethylase activity. Rim15 mediates the phosphorylation of Rph1 upon nitrogen starvation, which causes an inhibition of its function. Preventing Rph1 phosphorylation or overexpressing the protein causes a severe block in autophagy induction. A similar function of Rph1/KDM4 is seen in mammalian cells, indicating that this process is highly conserved. CONCLUSION:Rph1 maintains autophagy at a low level in nutrient-rich conditions; upon nutrient limitation, the inhibition of its activity is a prerequisite to the induction of ATG gene transcription and autophagy.
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