Surfactant phospholipid metabolism

Abstract

Pulmonary surfactant is essential for life and is composed of a complex lipoprotein-like mixture that lines the inner surface of the lung to prevent alveolar collapse at the end of expiration. The molecular composition of surfactant depends on highly integrated and regulated processes involving its biosynthesis, remodeling, degradation, and intracellular trafficking. Despite its multicomponent composition, the study of surfactant phospholipid metabolism has focused on two predominant components, disaturated phosphatidylcholine that confers surface-tension lowering activities, and phosphatidylglycerol, recently implicated in innate immune defense. Future studies providing a better understanding of the molecular control and physiological relevance of minor surfactant lipid components are needed. This article is part of a Special Issue entitled Phospholipids and Phospholipid Metabolism.

Fig. 1. Cartoon illustrating the composition of the pulmonary surfactant

The major surface-active phospholipid component is dipalmitoylphosphatidylcholine that interacts with key surfactant-associated proteins to lower surface tension. Phosphatidylglycerol is the second most abundant phospholipid that also modulates surface activity and may regulate innate immunity.

Fig 2. Cartoon illustrating biosynthetic pathways for pulmonary surfactant

A. Pathways for the major phospholipid components are shown including the de novo pathway for phosphatidylcholine (PC) synthesis. B. Cartoon illustrating modes of regulation and functional domains of cholinephosphate cytidylyltransferase α (CCTα), the key enzyme required for PC synthesis. CCTα is phosphorylated and its activity inhibited by extracellular signal regulated kinase (ERK_1/2). CCTα is also a protein that translocates between the cytoplasm and nucleus. This cytoplasmic/nuclear shuttling occurs via binding to the scaffolding protein, 14-3-3ζ. In this scenario, calmodulin kinase I (CaMKI) (red) phosphorylates CCTα thereby providing a phosphorylation dock site for 14-3-3ζ binding to the enzyme to facilitate nuclear import. Nuclear CCTα export is controlled by exportin 1 (CRM1) (blue). CCTα is also sensitive to proteolysis as it is monoubiquitinated (Ubi) at a molecular site juxtaposed near its nuclear localization signal (NLS). This post-translational mechanism limits the enzyme’s interaction with importin-α (Iα) thereby targeting the enzyme for degradation. Calpains also target CCTα for degradation, an effect antagonized by calmodulin (CaM). Many of these intermediate mechanisms are activated in cells by stimuli (TNFα, oxysterols, exogenous calcium). Last, CCTα regulated by both activating and inhibitory lipids. C. The remodeling pathway involves phospholipase A2 hydrolysis of an unsaturated PC yielding lyso-PC. This substrate is then re-acylated by LPCAT1 using palmitoyl-CoA generating dipalmitoylphosphatidylcholine. Adapted and modified from M. Hermansson et all/Progress in Lipid Research 50 (2011), 240–257.

Fig 2. Cartoon illustrating biosynthetic pathways for pulmonary surfactant

A. Pathways for the major phospholipid components are shown including the de novo pathway for phosphatidylcholine (PC) synthesis. B. Cartoon illustrating modes of regulation and functional domains of cholinephosphate cytidylyltransferase α (CCTα), the key enzyme required for PC synthesis. CCTα is phosphorylated and its activity inhibited by extracellular signal regulated kinase (ERK_1/2). CCTα is also a protein that translocates between the cytoplasm and nucleus. This cytoplasmic/nuclear shuttling occurs via binding to the scaffolding protein, 14-3-3ζ. In this scenario, calmodulin kinase I (CaMKI) (red) phosphorylates CCTα thereby providing a phosphorylation dock site for 14-3-3ζ binding to the enzyme to facilitate nuclear import. Nuclear CCTα export is controlled by exportin 1 (CRM1) (blue). CCTα is also sensitive to proteolysis as it is monoubiquitinated (Ubi) at a molecular site juxtaposed near its nuclear localization signal (NLS). This post-translational mechanism limits the enzyme’s interaction with importin-α (Iα) thereby targeting the enzyme for degradation. Calpains also target CCTα for degradation, an effect antagonized by calmodulin (CaM). Many of these intermediate mechanisms are activated in cells by stimuli (TNFα, oxysterols, exogenous calcium). Last, CCTα regulated by both activating and inhibitory lipids. C. The remodeling pathway involves phospholipase A2 hydrolysis of an unsaturated PC yielding lyso-PC. This substrate is then re-acylated by LPCAT1 using palmitoyl-CoA generating dipalmitoylphosphatidylcholine. Adapted and modified from M. Hermansson et all/Progress in Lipid Research 50 (2011), 240–257.

Fig 2. Cartoon illustrating biosynthetic pathways for pulmonary surfactant

A. Pathways for the major phospholipid components are shown including the de novo pathway for phosphatidylcholine (PC) synthesis. B. Cartoon illustrating modes of regulation and functional domains of cholinephosphate cytidylyltransferase α (CCTα), the key enzyme required for PC synthesis. CCTα is phosphorylated and its activity inhibited by extracellular signal regulated kinase (ERK_1/2). CCTα is also a protein that translocates between the cytoplasm and nucleus. This cytoplasmic/nuclear shuttling occurs via binding to the scaffolding protein, 14-3-3ζ. In this scenario, calmodulin kinase I (CaMKI) (red) phosphorylates CCTα thereby providing a phosphorylation dock site for 14-3-3ζ binding to the enzyme to facilitate nuclear import. Nuclear CCTα export is controlled by exportin 1 (CRM1) (blue). CCTα is also sensitive to proteolysis as it is monoubiquitinated (Ubi) at a molecular site juxtaposed near its nuclear localization signal (NLS). This post-translational mechanism limits the enzyme’s interaction with importin-α (Iα) thereby targeting the enzyme for degradation. Calpains also target CCTα for degradation, an effect antagonized by calmodulin (CaM). Many of these intermediate mechanisms are activated in cells by stimuli (TNFα, oxysterols, exogenous calcium). Last, CCTα regulated by both activating and inhibitory lipids. C. The remodeling pathway involves phospholipase A2 hydrolysis of an unsaturated PC yielding lyso-PC. This substrate is then re-acylated by LPCAT1 using palmitoyl-CoA generating dipalmitoylphosphatidylcholine. Adapted and modified from M. Hermansson et all/Progress in Lipid Research 50 (2011), 240–257.

Fig. 3. Cartoon illustrating sphingolipid metabolism

Biosynthesis is shown in red, degradation is shown in blue.

Fig. 4. Cartoon illustrating surfactant secretion, recycling, and catabolism

Surfactant is synthesized and secreted from distal lung alveolar type II epithelial cells using cellular substrates or from circulation. The newly synthesized surfactant phospholipids are packaged into a storage form, termed lamellar bodies. The secreted surface-active lipid material rapidly transforms into tubular myelin (not shown) that serves as a precursor to the monolayer film at the air-surface interface. During respiration, small and physiologically active large aggregates are formed that can be internalized and catabolized by alveolar cells, including macrophages. A significant portion of surfactant lipid is re-utilized by type II cells. Adapted and modified from M. Ikegami/Respirology 11 (2006), S24–S27.