PLAA/UFD-3 regulates P-bodies through its intrinsic disordered domain
Creators
-
1.
California Institute of Technology
Abstract
Regulation of proteome homeostasis is crucial for the survival and adaptation to changing environments for all species. In eukaryotes, this process is finely tuned through regulation at the level of transcription, translation, protein modification, and protein degradation. The phospholipase A2 activating protein (PLAA) is present in all eukaryotes and believed to be a key player in ubiquitin-dependent protein sorting and degradation via its interactions with ubiquitin and/or the AAA+ ATPase, valosin-containing protein (VCP/p97). PLAA’s molecular targets and interaction network remain unclear. We used Caenorhabditis elegans and unbiased proteome-scale approaches to investigate neuronal specific interactors of the C. elegans PLAA ortholog UFD-3 (ubiquitin fusion degradation 3), its effect on ubiquitinated proteins, and global protein expression changes in an ufd-3 mutant. We found that PLAA may play a unique role in cytoplasmic messenger ribonucleic acid (mRNA) processing bodies (P-bodies). Using biochemical analysis in vitro and fluorescence imaging in C. elegans, we show that UFD-3 directly interacts with the mRNA decapping complex regulatory subunit DCAP-1. UFD-3's intrinsic disordered region (IDR), which contains conserved amino acid motifs, is important for the recruitment of DCAP-1 to P-bodies. Finally, we show that loss of the IDR does not affect UFD-3's role in sorting ubiquitinated proteins through the multivesicular body pathway. Collectively, our results suggest that UFD-3's role in P-bodies is distinct from its role in the ubiquitin-dependent protein degradation pathway and the IDR is only critical for UFD-3-regulated P-bodies pathways. Thus, PLAA/UFD-3 might regulate the proteome via two distinct pathways: ubiquitinated protein turnover, as well as mRNA regulation through P-bodies.
Copyright and License
Copyright © 2025 the Author(s). Published by PNAS. This article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).
Acknowledgement
We thank Maureen Barr (Rutgers University) and John Cronan for providing valuable reagents. Some strains were provided by the Caenorhabditis Genetics Center, funded by NIH Office of Research Infrastructure Programs (P40-OD010440). WormBase, the Alliance of Genome Resources, and UniProt provided curated information. We thank members of our labs for discussions and comments, especially Chieh-Hsiang Tan and Hillel Schwartz. E.B. was an Amgen Summer Research Fellow. T.J.W. was supported by the Presidential Graduate Fellowship. Supported in part by R24OD023041 and 5U24HG002223 (P.W.S.). P.W.S. was a Bren Professor.
Funding
Some strains were provided by the Caenorhabditis Genetics Center, funded by NIH Office of Research Infrastructure Programs (P40-OD010440). E.B. was an Amgen Summer Research Fellow. T.J.W. was supported by the Presidential Graduate Fellowship. Supported in part by R24OD023041 and 5U24HG002223 (P.W.S.). P.W.S. was a Bren Professor.
Contributions
A.D., Y.Q., T.J.W., E.B., J.C., H.P., T.-F.C., and P.W.S. designed research; A.D., Y.Q., T.J.W., E.B., H.P., and E.C.C. performed research; A.D. and H.P. contributed new reagents/analytic tools; A.D., Y.Q., T.J.W., E.B., J.C., H.P., and T.-F.C. analyzed data; and A.D., Y.Q., T.J.W., T.-F.C., and P.W.S. wrote the paper.
Data Availability
Proteomics data have been deposited in PRIDE (PXD059010) (82).
Conflict of Interest
The authors declare no competing interest.
Supplemental Material
Appendix 01 (PDF)
Dataset S01 (XLSX)
Dataset S02 (XLSX)
Dataset S03 (XLSX)
Files
das-et-al-2025-plaa-ufd-3-regulates-p-bodies-through-its-intrinsic-disordered-domain.pdf
Files
(13.5 MB)
| Name | Size | Download all |
|---|---|---|
|
md5:f6c5df1f8646c901b8d98794830240d3
|
1.6 MB | Preview Download |
|
md5:0e5c66b2a5bab25037a3a27a48d74d12
|
522.3 kB | Preview Download |
|
md5:1bdb80bbad291f1034d20be4c350e665
|
5.7 MB | Download |
|
md5:6c99f0c476ef5ac71f55529d5f724f20
|
2.7 MB | Download |
|
md5:ff06c5ce5d9e3085592349175b52cc22
|
3.0 MB | Download |
Additional details
Identifiers
- PMID
- 40560612
- PMCID
- PMC12232612
Related works
- Describes
- Journal Article: 40560612 (PMID)
- Journal Article: PMC12232612 (PMCID)
- Is supplemented by
- Dataset: https://www.ebi.ac.uk/pride/archive/projects/PXD059010 (URL)
Funding
- Office of Research Infrastructure Programs
- P40-OD010440
- Amgen (United States)
- National Institutes of Health
- R24OD023041
- National Human Genome Research Institute
- 5U24HG002223
Dates
- Submitted
-
2024-12-31
- Accepted
-
2025-05-16
- Available
-
2025-06-25Published online