O-GlcNAc-Modification of NSL3 at Thr755 Site Maintains the Holoenzyme Activity of MOF/NSL Histone Acetyltransferase Complex
O-GlcNAc-Modification of NSL3 at Thr755 Site Maintains the Holoenzyme Activity of MOF/NSL Histone Acetyltransferase Complex
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DOI：
10.3390/ijms21010173
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Jingji Jin
中科院分区：
文献类型：
--
作者：
Linhong Zhao;Min Li;Tao Wei;Chang Feng;Tingting Wu;Junaid Ali Shah;Hongsen Liu;Fei Wang;Yong Cai;Jingji Jin
Both OGT1 (O-linked β-N-acetylglucosamine (O-GlcNAc) transferase isoform 1) and NSL3.(nonspecific lethal protein 3) are crucial components of the MOF (males absent on the first)/NSL histone.acetyltransferase complex. We previously described how global histone H4 acetylation levels were.modulated by OGT1/O-GlcNAcylation-mediated NSL3 stability. However, the specific modification.site of NSL3 and its molecular mechanism of protein stability remain unknown. Here, we present.evidence from biochemical experiments arguing that O-GlcNAcylation of NSL3 at Thr755 is tightly.associated with holoenzyme activity of the MOF/NSL complex. Using in vitro O-GlcNAc-transferase.assays combined with mass spectrometry, we suppose that the residue Thr755 on NSL3 C-terminus is.the major site O-GlcNAc-modified by OGT1. Importantly, O-GlcNAcylation of this site is involved in.the regulation of the ubiquitin-degradation of NSL3, because this site mutation (T755A) promotes the.ubiquitin-mediated degradation of NSL3. Further in-depth research found that ubiquitin conjugating.enzyme E2 S (UBE2S) accelerated the degradation of NSL3 via direct binding to it. Interestingly,.OGT1 and UBE2S competitively bind to NSL3, suggesting the coordination of OGT1–UBE2S in.regulating NSL3 stability. Furthermore, O-GlcNAcylation of NSL3 Thr755 site regulates the histone.H4 acetylation levels at lysine 5, 8, and 16, suggesting that the O-GlcNAcylation of NSL3 at Thr755 is.required for maintaining the integrity and holoenzyme activity of the MOF/NSL complex. In colony.formation assays, we found that the integrity of the complex impacts the proliferation of the lung.carcinoma type II epithelium-like A549 cells. Taken together, our results provide new insight into the.elucidation of the molecular mechanism of the MOF/NSL complex.
