biostudies-literatureUnknown28(5)Kang SWKorea Ministry of Science and ICTPeptidyl-prolyl <i>cis/trans</i> isomerases (PPIases) accelerate proline peptide bond isomerization, affecting substrate protein function. In this study, through RNAi-based behavioral screening of PPIases in <i>Drosophila melanogaster</i>, we identified <i>CG5808</i>, termed <i>Drosophila</i> peptidyl-prolyl <i>cis/trans</i> isomerase-like 4 (dPPIL4), as crucial for circadian rhythm regulation. Knockdown of <i>dppil4</i> in clock cells lengthened the circadian rhythm period and decreased rhythmicity, accompanied by a significant reduction of core clock protein PERIOD (PER). <i>d</i> <i>ppil4</i> knockdown downregulated <i>per</i> transcription and reduced phosphorylation at Ser5 in the RNA polymerase II C-terminal domain, critical for transcription elongation. In addition, dPPIL4 stabilizeiScience112457https://www.ebi.ac.uk/biostudies/studies/S-EPMC12084006biostudies-literature<i>Drosophila</i> peptidyl-prolyl <i>cis/trans</i> isomerase-like 4 regulates circadian rhythm by supporting high-amplitude oscillations of PERIOD.PMC12084006Kim EYKang SWLim SBNg JTTran HTLee Gfalse<i>Drosophila</i> peptidyl-prolyl <i>cis/trans</i> isomerase-like 4 regulates circadian rhythm by supporting high-amplitude oscillations of PERIOD.Peptidyl-prolyl <i>cis/trans</i> isomerases (PPIases) accelerate proline peptide bond isomerization, affecting substrate protein function. In this study, through RNAi-based behavioral screening of PPIases in <i>Drosophila melanogaster</i>, we identified <i>CG5808</i>, termed <i>Drosophila</i> peptidyl-prolyl <i>cis/trans</i> isomerase-like 4 (dPPIL4), as crucial for circadian rhythm regulation. Knockdown of <i>dppil4</i> in clock cells lengthened the circadian rhythm period and decreased rhythmicity, accompanied by a significant reduction of core clock protein PERIOD (PER). <i>d</i> <i>ppil4</i> knockdown downregulated <i>per</i> transcription and reduced phosphorylation at Ser5 in the RNA polymerase II C-terminal domain, critical for transcription elongation. In addition, dPPIL4 stabilize2025-01-01T00:00:00Z2025 May2026-06-01T14:45:19.27Z2026-04-08T13:24:00.27ZS-EPMC120840064038493410.1016/j.isci.2025.112457