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E3 ubiquitin ligase recognizes its protein substrates via specific molecular signatures for ubiquitin proteasomal degradation. However, the role of acetylation/ deacetylation in the process of E3 ubiquitin ligase recognizing its protein substrate is not fully studied. Here we report that a tandem IK motif in protein arginine methyltransferase 1 (PRMT1) forms an acetyldegron to recruit ubiquitin E3 ligase SCF (Skp1-Cullin1-Fbox protein)-Fbxl17. PRMT1 is poly-ubiquitinated for proteasome degradation with a half-life of approximate 4 h in lung epithelial cells. SCF-Fbxl17 mediates PRMT1 poly-ubiquitination at K117. SCF-Fbxl17 specifically binds PRMT1 via a unique motif IKXXXIK. Strikingly, acetylation/deacetylation status of the lysine residues within the motif determines Fbxl17 binding. Deacetylation on both K200 and K205 by Surtuin1 (Sirt1) and acetylation of p300 on K205 collaboratively prepare the motif for SCF-Fbxl17 binding thereby trigger PRMT1 protein degradation. Pathogen-derived lipopolysaccharide (LPS) down regulates Sirt1 and p300 to protect PRMT1 from degradation. This study demonstrates that LPS promotes PRMT1 stability by blockade of PRMT1 and SCF-Fbxl17 binding via an acetylation/deacetylation-modified acetyldegron to attribute to bronchial epithelial cell overgrowth in pulmonary inflammatory diseases.

LPS modulates p300 and Sirt1 to promote PRMT1 stability via a SCF-Fbxl17-recognized acetyldegron