AUTHOR=Pablo Tortola Cristina , Fielitz Britta , Li Yi , Rüdebusch Julia , Luft Friedrich C. , Fielitz Jens 

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

JOURNAL=Frontiers in Physiology

VOLUME=11

YEAR=2021

URL=https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2020.550506

DOI=10.3389/fphys.2020.550506

ISSN=1664-042X

ABSTRACT=<sec><title>Rationale</title><p>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)/<italic>tripartite motif-containing 63</italic> (<italic>TRIM63</italic>) expression. MuRF 1 ubiquitinates structural proteins and mediates their UPS-dependent degradation. We now investigated how TFEB-mediated <italic>TRIM63</italic> expression is regulated.</p></sec><sec><title>Objective</title><p>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 <italic>TRIM63</italic> expression.</p></sec><sec><title>Methods and Results</title><p>We found that TFEB and transcription factor for immunoglobulin heavy-chain enhancer 3 (TFE3) activate <italic>TRIM63</italic> 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.</p></sec><sec><title>Conclusion</title><p>TFEB and TFE3 activate <italic>TRIM63</italic> 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 <italic>TRIM63</italic> expression.</p></sec>