PTEN directly activates the actin depolymerization factor cofilin-1 during PGE2-mediated inhibition of phagocytosis of fungi.
Macrophage ingestion of the yeast Candida albicans requires its recognition by multiple receptors and the activation of diverse signaling programs. Synthesis of the lipid mediator prostaglandin E(2) (PGE(2)) and generation of cyclic adenosine monophosphate (cAMP) also accompany this process. Here, we characterized the mechanisms underlying PGE(2)-mediated inhibition of phagocytosis and filamentous actin (F-actin) polymerization in response to ingestion of C. albicans by alveolar macrophages. PGE(2) suppressed phagocytosis and F-actin formation through the PGE(2) receptors EP2 and EP4, cAMP, and activation of types I and II protein kinase A. Dephosphorylation and activation of the actin depolymerizing factor cofilin-1 were necessary for these inhibitory effects of PGE(2). PGE(2)-dependent activation of cofilin-1 was mediated by the protein phosphatase activity of PTEN (phosphatase and tensin homolog deleted on chromosome 10), with which it directly associated. Because enhanced production of PGE(2) accompanies many immunosuppressed states, the PTEN-dependent pathway described here may contribute to impaired antifungal defenses.
Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI 48109, USA.
C Henrique
CH
Serezani
Steve
S
Kane
Alexandra I
AI
Medeiros
Ashley M
AM
Cornett
Sang-Hoon
SH
Kim
Mariana Morato
MM
Marques
Sang-Pyo
SP
Lee
Casey
C
Lewis
Emilie
E
Bourdonnay
Megan N
MN
Ballinger
Eric S
ES
White
Marc
M
Peters-Golden
D000199:Actins / Q000276:immunology / Q000378:metabolism; D000818:Animals; D002176:Candida albicans / Q000276:immunology* / Q000378:metabolism; D002177:Candidiasis / Q000276:immunology* / Q000378:metabolism; D002478:Cells, Cultured; D051338:Cofilin 1 / Q000276:immunology* / Q000378:metabolism; D000242:Cyclic AMP / Q000276:immunology / Q000378:metabolism; D054743:Cyclic AMP-Dependent Protein Kinase Type I / Q000276:immunology / Q000378:metabolism; D054746:Cyclic AMP-Dependent Protein Kinase Type II / Q000276:immunology / Q000378:metabolism; D015232:Dinoprostone / Q000096:biosynthesis / Q000276:immunology*; D005260:Female; D007108:Immune Tolerance; D016676:Macrophages, Alveolar / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D051059:PTEN Phosphohydrolase / Q000276:immunology* / Q000378:metabolism; D010587:Phagocytosis / Q000276:immunology*; D010766:Phosphorylation / Q000276:immunology; D051381:Rats; D017208:Rats, Wistar; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000276:immunology / Q000378:metabolism; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000276:immunology / Q000378:metabolism
D000199:Actins; C495812:Cfl1 protein, rat; D051338:Cofilin 1; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D000242:Cyclic AMP; D054743:Cyclic AMP-Dependent Protein Kinase Type I; D054746:Cyclic AMP-Dependent Protein Kinase Type II; D051059:PTEN Phosphohydrolase; C487216:Pten protein, rat; D015232:Dinoprostone