LPS Impairs Phospholipid Synthesis by Triggering β-Transducin Repeat-containing Protein (β-TrCP)-mediated Polyubiquitination and Degradation of the Surfactant Enzyme Acyl-CoA:Lysophosphatidylcholine Acyltransferase I (LPCAT1)

• DOI: 10.1074/jbc.m110.192377
• Publication Date: 2010-11-12T01:13:28Z
• Authors: Chunbin Zou; Phillip L. Butler; Tiffany A. Coon; Rebecca M. Smith; Gary Hammen; Yutong Zhao; Bill B. Chen; Rama K. Mallampalli
• Keywords: Acyltransferases; Cullin

Acyl-CoA:lysophosphatidylcholine acyltransferase 1 (LPCAT1) is a relatively newly described and yet indispensable enzyme needed for generation of the bioactive surfactant phospholipid, dipalmitoylphosphatidylcholine (DPPtdCho). Here, we show that lipopolysaccharide (LPS) causes LPCAT1 degradation using Skp1-Cullin-F-box ubiquitin E3 ligase component, β-transducin repeat-containing protein (β-TrCP), polyubiquitinates LPCAT1, thereby targeting proteasomal degradation. was identified as phosphoenzyme Ser178 within phosphodegron putative molecular recognition site glycogen synthase kinase-3β (GSK-3β) phosphorylation recruits β-TrCP docking enzyme. ubiquitinates at an acceptor (Lys221), substitution Lys221 with Arg abrogated polyubiquitination. LPS profoundly reduced immunoreactive levels impaired lung mechanics, effects were overcome by siRNA to GSK-3β or gene transfer, respectively. Thus, appears destabilize GSK-3β-mediated canonical site-specific ubiquitination. first lipogenic substrate β-TrCP, results suggest modulation GSK-3β-SCFβTrCP effector pathway might be unique strategy optimize in sepsis.