Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
4
pubmed:dateCreated
2011-1-24
pubmed:abstractText
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 the Skp1-Cullin-F-box ubiquitin E3 ligase component, ?-transducin repeat-containing protein (?-TrCP), that polyubiquitinates LPCAT1, thereby targeting the enzyme for proteasomal degradation. LPCAT1 was identified as a phosphoenzyme as Ser(178) within a phosphodegron was identified as a putative molecular recognition site for glycogen synthase kinase-3? (GSK-3?) phosphorylation that recruits ?-TrCP docking within the enzyme. ?-TrCP ubiquitinates LPCAT1 at an acceptor site (Lys(221)), as substitution of Lys(221) with Arg abrogated LPCAT1 polyubiquitination. LPS profoundly reduced immunoreactive LPCAT1 levels and impaired lung surfactant mechanics, effects that were overcome by siRNA to ?-TrCP and GSK-3? or LPCAT1 gene transfer, respectively. Thus, LPS appears to destabilize the LPCAT1 protein by GSK-3?-mediated phosphorylation within a canonical phosphodegron for ?-TrCP docking and site-specific ubiquitination. LPCAT1 is the first lipogenic substrate for ?-TrCP, and the results suggest that modulation of the GSK-3?-SCF?(TrCP) E3 ligase effector pathway might be a unique strategy to optimize dipalmitoylphosphatidylcholine levels in sepsis.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
http://linkedlifedata.com/resource/pubmed/chemical/1,2-Dipalmitoylphosphatidylcholine, http://linkedlifedata.com/resource/pubmed/chemical/1-Acylglycerophosphocholine..., http://linkedlifedata.com/resource/pubmed/chemical/Glycogen Synthase Kinase 3, http://linkedlifedata.com/resource/pubmed/chemical/Lipopolysaccharides, http://linkedlifedata.com/resource/pubmed/chemical/Lpcat1 protein, mouse, http://linkedlifedata.com/resource/pubmed/chemical/Proteasome Endopeptidase Complex, http://linkedlifedata.com/resource/pubmed/chemical/Pulmonary Surfactants, http://linkedlifedata.com/resource/pubmed/chemical/SKP Cullin F-Box Protein Ligases, http://linkedlifedata.com/resource/pubmed/chemical/beta-Transducin Repeat-Containing..., http://linkedlifedata.com/resource/pubmed/chemical/glycogen synthase kinase 3 beta
pubmed:status
MEDLINE
pubmed:month
Jan
pubmed:issn
1083-351X
pubmed:author
pubmed:issnType
Electronic
pubmed:day
28
pubmed:volume
286
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
2719-27
pubmed:dateRevised
2011-11-2
pubmed:meshHeading
pubmed-meshheading:21068446-1,2-Dipalmitoylphosphatidylcholine, pubmed-meshheading:21068446-1-Acylglycerophosphocholine O-Acyltransferase, pubmed-meshheading:21068446-Animals, pubmed-meshheading:21068446-Cells, Cultured, pubmed-meshheading:21068446-Enzyme Stability, pubmed-meshheading:21068446-Glycogen Synthase Kinase 3, pubmed-meshheading:21068446-Lipopolysaccharides, pubmed-meshheading:21068446-Mice, pubmed-meshheading:21068446-Phosphorylation, pubmed-meshheading:21068446-Proteasome Endopeptidase Complex, pubmed-meshheading:21068446-Pulmonary Surfactants, pubmed-meshheading:21068446-Respiratory Mucosa, pubmed-meshheading:21068446-SKP Cullin F-Box Protein Ligases, pubmed-meshheading:21068446-Sepsis, pubmed-meshheading:21068446-Ubiquitination, pubmed-meshheading:21068446-beta-Transducin Repeat-Containing Proteins
pubmed:year
2011
pubmed:articleTitle
LPS impairs phospholipid synthesis by triggering beta-transducin repeat-containing protein (beta-TrCP)-mediated polyubiquitination and degradation of the surfactant enzyme acyl-CoA:lysophosphatidylcholine acyltransferase I (LPCAT1).
pubmed:affiliation
Department of Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, N.I.H., Extramural