Phosphorylation of RPT6 Controls Its Ability to Bind DNA and Regulate Gene Expression in the Hippocampus of Male Rats during Memory Formation
| dc.contributor.author | Farrell, Kayla | en |
| dc.contributor.author | Auerbach, Aubrey | en |
| dc.contributor.author | Musaus, Madeline | en |
| dc.contributor.author | Navabpour, Shaghayegh | en |
| dc.contributor.author | Liu, Catherine | en |
| dc.contributor.author | Lin, Yu | en |
| dc.contributor.author | Xie, Hehuang | en |
| dc.contributor.author | Jarome, Timothy J. | en |
| dc.date.accessioned | 2024-01-25T20:43:51Z | en |
| dc.date.available | 2024-01-25T20:43:51Z | en |
| dc.date.issued | 2024-01 | en |
| dc.description.abstract | Memory formation requires coordinated control of gene expression, protein synthesis, and ubiquitin–proteasome system (UPS)-mediated protein degradation. The catalytic component of the UPS, the 26S proteasome, contains a 20S catalytic core surrounded by two 19S regulatory caps, and phosphorylation of the 19S cap regulatory subunit RPT6 at serine 120 (pRPT6-S120) has been widely implicated in controlling activity-dependent increases in proteasome activity. Recently, RPT6 was also shown to act outside the proteasome where it has a transcription factor-like role in the hippocampus during memory formation. However, little is known about the proteasome-independent function of “free” RPT6 in the brain or during memory formation and whether phosphorylation of S120 is required for this transcriptional control function. Here, we used RNA-sequencing along with novel genetic approaches and biochemical, molecular, and behavioral assays to test the hypothesis that pRPT6-S120 functions independently of the proteasome to bind DNA and regulate gene expression during memory formation. RNA-sequencing following siRNA-mediated knockdown of free RPT6 revealed 46 gene targets in the dorsal hippocampus of male rats following fear conditioning, where RPT6 was involved in transcriptional activation and repression. Through CRISPR-dCas9-mediated artificial placement of RPT6 at a target gene, we found that RPT6 DNA binding alone may be important for altering gene expression following learning. Further, CRISPR-dCas13-mediated conversion of S120 to glycine on RPT6 revealed that phosphorylation at S120 is necessary for RPT6 to bind DNA and properly regulate transcription during memory formation. Together, we reveal a novel function for phosphorylation of RPT6 in controlling gene transcription during memory formation. | en |
| dc.description.sponsorship | This work was supported by National Institutes of Health grants MH122414, MH131587, MH120498, MH120569, MH123742, AG071523, and AG079292 to T.J.J. | en |
| dc.format.mimetype | application/pdf | en |
| dc.identifier.doi | https://doi.org/10.1523/JNEUROSCI.1453-23.2023 | en |
| dc.identifier.issue | 4 | en |
| dc.identifier.uri | https://hdl.handle.net/10919/117688 | en |
| dc.identifier.volume | 44 | en |
| dc.language.iso | en | en |
| dc.publisher | Society for Neuroscience | en |
| dc.subject | CRISPR | en |
| dc.subject | Hippocampus | en |
| dc.subject | memory | en |
| dc.subject | proteasome | en |
| dc.subject | RPT6 | en |
| dc.subject | transcription | en |
| dc.title | Phosphorylation of RPT6 Controls Its Ability to Bind DNA and Regulate Gene Expression in the Hippocampus of Male Rats during Memory Formation | en |
| dc.title.serial | Journal of Neuroscience | en |
| dc.type | Article - Refereed | en |
| dc.type.dcmitype | Text | en |