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Activation of tripartite motif containing 63 expression by transcription factor EB and transcription factor binding to immunoglobulin heavy chain enhancer 3 is regulated by protein kinase D and class IIa histone deacetylases

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Item Type:Article
Title:Activation of tripartite motif containing 63 expression by transcription factor EB and transcription factor binding to immunoglobulin heavy chain enhancer 3 is regulated by protein kinase D and class IIa histone deacetylases
Creators Name:Pablo Tortola, C. and Fielitz, B. and Li, Y. and Rüdebusch, J. and Luft, F.C. and Fielitz, J.
Abstract:RATIONALE: The ubiquitin-proteasome system (UPS) is responsible for skeletal muscle atrophy. We showed earlier that the transcription factor EB (TFEB) plays a role by increasing E3 ubiquitin ligase muscle really interesting new gene-finger 1(MuRF1)/tripartite motif-containing 63 (TRIM63) expression. MuRF 1 ubiquitinates structural proteins and mediates their UPS-dependent degradation. We now investigated how TFEB-mediated TRIM63 expression is regulated. OBJECTIVE: Because protein kinase D1 (PKD1), histone deacetylase 5 (HDAC5), and TFEB belong to respective families with close structural, regulatory, and functional properties, we hypothesized that these families comprise a network regulating TRIM63 expression. METHODS AND RESULTS: We found that TFEB and transcription factor for immunoglobulin heavy-chain enhancer 3 (TFE3) activate TRIM63 expression. The class IIa HDACs HDAC4, HDAC5, and HDAC7 inhibited this activity. Furthermore, we could map the HDAC5 and TFE3 physical interaction. PKD1, PKD2, and PKD3 reversed the inhibitory effect of all tested class IIa HDACs toward TFEB and TFE3. PKD1 mediated nuclear export of all HDACs and lifted TFEB and TFE3 repression. We also mapped the PKD2 and HDAC5 interaction. We found that the inhibitory effect of PKD1 and PKD2 toward HDAC4, HDAC5, and HDAC7 was mediated by their phosphorylation and 14-3-3 mediated nuclear export. CONCLUSION: TFEB and TFE3 activate TRIM63 expression. Both transcription factors are controlled by HDAC4, HDAC5, HDAC7, and all PKD-family members. We propose that the multilevel PKD/HDAC/TFEB/TFE3 network tightly controls TRIM63 expression.
Keywords:Muscle Atrophy, Protein Kinase D, HDAC = Histone Deacetylase, Transcription Factor EB, TFE3, Muscle Ring Finger Protein 1
Source:Frontiers in Physiology
ISSN:1664-042X
Publisher:Frontiers Media SA
Volume:11
Page Range:550506
Date:13 January 2021
Official Publication:https://doi.org/10.3389/fphys.2020.550506
PubMed:View item in PubMed

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