Regulation of SRF protein stability by an autophagy-dependent pathway

Abstract

Serum response factor (SRF), a key transcription factor, plays an important role in regulating cell functions such as proliferation and differentiation. Most proteins are unstable, and protein stability is regulated through the ubiquitin-proteasome system (UPS) or the autophagy lysosome pathway (ALP). Whether SRF is degraded and what mechanisms control SRF protein stability remain unexplored. Western blot analyses of cells treated with cycloheximide (CHX), a protein synthesis inhibitor, showed that SRF was degraded in a time-dependent manner. Moreover, we observed that SRF undergoes autophagy-dependent destruction, which is accelerated by serum deprivation. Through bioinformatics screening, we found that SRF contains the GSK3β phosphorylation motif (T/SPPXS): SPDSPPRSDPT, which is conserved from zebrafish to humans. Serum deprivation stimulated GSK3β activation that then potentiates SRF degradation through the autophagy lysosome pathway. Since SRF is important for numerous cellular activities, our results suggest that the autophagy-dependent SRF degradation pathway may provide a new avenue to modulate SRFmediated cell functions.

Repositioning of ezetimibe for the treatment of idiopathic pulmonary fibrosis

“…This is consistent with our observation that SRF is largely expressed in myofibroblast nuclei in our cell and mouse models. Another study demonstrated that SRF is degraded via autophagy rather than the ubiquitin-proteasome pathway [ 36 ]. Our experiments support this, having shown that SRF was degraded by ezetimibe-activated autophagy and accumulated during autophagy inhibition.…”

SRF deletion results in earlier disease onset in a mouse model of amyotrophic lateral sclerosis

“…However, this also implies that other TFs such as CREB- ( 57 ) or SRF-directed IEGs known to regulate autophagy ( 58 , 59 ) might provide a link between neuronal activity and autophagy gene regulation. So far, only 2 instances of an SRF connection with autophagy have been reported ( 60 , 61 ). Here, SRF protected MNs from rotenone-induced cellular death and reduced synuclein aggregation; however, this beneficial effect was abolished by either Beclin1 or Atg5 knockdown, implying that autophagy induction is a critical component of the neuroprotective SRF effects ( 60 ).…”

“…This cell culture finding supports our conclusion that, in response to neuronal activity, SRF modulates autophagy to convey neuroprotection. Finally, SRF was shown to be subject to autophagy-dependent degradation ( 61 ). This points at a reciprocal regulatory mechanism whereby SRF might regulate mRNA abundance of autophagy-encoding genes.…”

Unveiling the Probiotic Potential of the Anaerobic Bacterium Cetobacterium sp. nov. C33 for Enhancing Nile Tilapia (Oreochromis niloticus) Cultures

“…RefSeq (NCBI Reference Sequence Database) was used to obtain the reference genomes of the bacteria. The assembled contigs were then loaded with their respective reference genomes into Medusa (http://combo.dbe.unifi.it/medusa (accessed on 20 July 2023)) [21] to determine the orientation and the order among the contigs to produce longer scaffolds [22,23]. The genome sequence data was uploaded to the Type Strain Genome Server (TYGS), a free bioinformatics platform available at https://tygs.dsmz.de (accessed on 26 July 2023), for full genome-based taxonomic analysis [24] and, for the determination of closely related type strains, a pairwise comparison of genomic sequences, phylogenetic inferences, and grouping of species and subspecies based on the type [24].…”