ORCID
- Justyna Lopatecka: 0000-0003-3980-077X
- Holly N. Stephenson: 0000-0002-8121-9252
- Gyorgy Fejer: 0000-0001-6761-0506
- Vikram Sharma: 0000-0002-3833-7763
- Shouqing Luo: 0000-0002-7998-3059
Abstract
Autophagy and ribonucleoprotein granules, such as P-bodies (PBs) and stress granules, represent vital stress responses to maintain cellular homeostasis. SQSTM1/p62 phase-separated droplets are known to play critical roles in selective autophagy; however, it is unknown whether p62 can exist as another form in addition to its autophagic droplets. Here, we found that, under stress conditions, including proteotoxicity, endotoxicity, and oxidation, autophagic p62 droplets are transformed to a type of enlarged PBs, termed p62-dependent P-bodies (pd-PBs). p62 phase separation is essential for the nucleation of pd-PBs. Mechanistically, pd-PBs are triggered by enhanced p62 droplet formation upon stress stimulation through the interactions between p62 and DDX6, a DEAD-box ATPase. Functionally, pd-PBs recruit the NLRP3 inflammasome adaptor ASC to assemble the NLRP3 inflammasome and induce inflammation-associated cytotoxicity. Our study shows that p62 droplet-to-PB transformation acts as a stress response to activate the NLRP3 inflammasome process, suggesting that persistent pd-PBs lead to NLRP3-dependent inflammation toxicity.
DOI
10.1016/j.celrep.2024.113935
Publication Date
2024-03-26
Publication Title
Cell Reports
Volume
43
Issue
3
ISSN
2211-1247
Keywords
ASC/PYCARD, autophagy, CP: Molecular biology, liquid-liquid phase separation, LLPS, NLRP3 inflammasome, P-bodies, RNP granules, SQSTM1/p62, stress granules
Recommended Citation
Lu, B., Luo, S., Barrow, E., Valionyte, E., Baxter, C., Yang, Y., Herath, S., O'Connell, W., Lopatecka, J., Strachan, A., Woznica, W., Stephenson, H., Fejer, G., & Sharma, V. (2024) 'Discovery of SQSTM1/p62-dependent P-bodies that regulate the NLRP3 inflammasome', Cell Reports, 43(3). Available at: https://doi.org/10.1016/j.celrep.2024.113935
