Abstract
RationaleThe 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.ObjectiveBecause 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 ResultsWe 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.ConclusionTFEB 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.
Highlights
Muscle mass is mainly regulated by an equilibrium of protein synthesis and degradation
We showed that inhibition of transcription factor EB (TFEB) by HDAC5 was attenuated by the stress-dependent serine/threonine kinase protein kinase D (PKD) 1, which interacted with HDAC5 and mediated its phosphorylation and 14-3-3 chaperone mediated nuclear export
We showed that TFEB transcriptional activity was attenuated by HDAC5 that physically interacted and colocalized with TFEB in myocytes in vitro (Du Bois et al, 2015)
Summary
Muscle mass is mainly regulated by an equilibrium of protein synthesis and degradation. Both muscle atrophy and hypertrophy occur physiologically and under disease conditions (Hershko and Ciechanover, 1998; Ciechanover, 2006; Schmidt et al, 2014; Wollersheim et al, 2014). MuRF1 was shown to mediate ubiquitination and UPS-dependent degradation of structural proteins, such as alpha-actin, troponin I, troponin T, telethonin, titin, nebulin, the nebulin-related-anchoring protein, myosin light chain 2, myotilin, and T-cap (Kedar et al, 2004; Witt et al, 2005; Polge et al, 2011, 2018). To evaluate the transcriptional control of TRIM63, we performed a complementary DNA (cDNA)-expression screen to identify
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