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Lipid-anchored proteasomes control membrane protein homeostasis
Ruizhu Zhang1, Shuxian Pan1, Suya Zheng1
1Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China.
Science Advances
|November 29, 2023
Summary
Myristoylation of Rpt2 anchors proteasomes to membranes, crucial for cellular processes. Loss of this anchors impairs protein homeostasis, leading to embryonic lethality and suppressed tumor growth.
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- Protein degradation is vital in eukaryotic cells, primarily mediated by the 26S proteasome.
- The role of proteasome membrane association and anchoring mechanisms in higher organisms remained largely unexplored.
Purpose of the Study:
- To elucidate the mechanism of proteasome anchoring to cellular membranes.
- To investigate the biological significance of proteasome-membrane interactions in eukaryotic cells.
Main Methods:
- Utilized N-myristoylation of the Rpt2 subunit as a focus for proteasome-membrane interaction studies.
- Generated and analyzed Rpt2-G2A mutant cells to assess the impact of lost myristoylation.
- Investigated the effects of Rpt2 mutation on the membrane-associated proteome and cellular processes.
- Examined the in vivo consequences of Rpt2 homozygous mutation in a mouse model and a xenograft tumor model.
Main Results:
- Identified N-myristoylation of the Rpt2 subunit as a key mechanism for proteasome-membrane anchoring.
- Demonstrated that loss of Rpt2 myristoylation profoundly alters the membrane proteome.
- Observed perturbation of the endomembrane system and critical cellular functions, including ER-associated degradation and membrane protein trafficking.
- Found that homozygous Rpt2(G2A/G2A) mutation causes embryonic lethality in mice and inhibits tumor growth.
Conclusions:
- Established an evolutionarily conserved mechanism for maintaining membrane protein homeostasis via myristoyl-anchored proteasomes.
- Highlighted the importance of compartmentalized protein degradation for cellular function, health, and disease.
- Underscored the therapeutic potential of targeting proteasome-membrane interactions.
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