Pneumonia remains the leading cause of infectious deaths and yet fundamentally new conceptual models underlying its pathogenesis have not emerged. Patients and mice with bacterial pneumonia have marked elevations of cardiolipin in lung fluid, a rare, mitochondrial-specific phospholipid that potently disrupts surfactant function. Intratracheal cardiolipin in mice recapitulates the clinical phenotype of pneumonia including impaired lung mechanics, modulation of cell survival and cytokine networks, and lobar consolidation. We have identified and characterized the activity of a novel cardiolipin transporter, ATP8b1, a mutant version of which is associated with severe pneumonia in humans and mice. ATP8b1 bound and internalized cardiolipin from extracellular fluid via a basic residue-enriched motif. Administration of cardiolipin binding motif peptide or ATP8b1 gene transfer in mice lessened lung injury and improved survival. The results unveil a new paradigm whereby ATP8b1 is a cardiolipin importer but its capacity to remove cardiolipin from lung fluid is exceeded during inflammation or ATP8b1 inefficiency. This discovery opens the door for new therapeutic strategies directed at modulating cardiolipin levels or its molecular interactions in pneumonia.

A study on the bonding in bis-pyridine halonium cations has been carried out using both theoretical and synthetic techniques. The primary thrust for the study is to highlight the opportunities potentially afforded by considering iodine as a Lewis acid in a classic coordination sense. Our results suggest that the iodine dipyridine complex ([pyr-I-pyr]+) can be considered as a coordination complex of [I]+. The lighter bromine and chlorine analogues are more towards the covalent rather than the dative side of bonding, while [pyr-F-pyr]+ is best described as an ion-molecule complex with one strong covalent F-pyr bond and one weak F-pyr dispersion interaction. Finally, theoretical and synthetic studies suggest that the commercially available [pyr-F]+ cation cannot be considered as a coordination complex of ‘F+’, despite its use as a source of electrophilic fluorine.

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.

Background: Ubiquitination controls trafficking of the epithelial Na ϩ channel (ENaC) in the endocytic pathway.

Phosphatidylcholine (PtdCho), the major phospholipid of animal membranes, is generated by its remodeling and de novo synthesis. Overexpression of the remodeling enzyme, LPCAT1 (acyl-CoA:lysophosphatidylcholine acyltransferase) in epithelia decreased de novo PtdCho synthesis without significantly altering cellular PtdCho mass. Overexpression of LPCAT1 increased degradation of CPT1 (cholinephosphotransferase), a resident Golgi enzyme that catalyzes the terminal step for de novo PtdCho synthesis. CPT1 degradation involved its multiubiquitination and processing via the lysosomal pathway. CPT1 mutants harboring arginine substitutions at multiple carboxyl-terminal lysines exhibited proteolytic resistance to effects of LPCAT1 overexpression in cells and restored de novo PtdCho synthesis. Thus, cross-talk between phospholipid remodeling and de novo pathways involves ubiquitin-lysosomal processing of a key molecular target that mechanistically provides homeostatic control of cellular PtdCho content.