Surfactant Protein D (Sp-D) Binds to Membrane-proximal Domain (D3) of Signal Regulatory Protein α (SIRPα), a Site Distant from Binding Domain of CD47, while Also Binding to Analogous Region on Signal Regulatory Protein β (SIRPβ)

Fournier, Bénédicte; Andargachew, Rakieb; Robin, Alexander Z.; Laur, Oskar; Voelker, Dennis R.; Lee, Winston Y.; Weber, Dominique A.; Parkos, Charles A.

doi:10.1074/jbc.m111.324533

Cited by 21 publications

(15 citation statements)

References 47 publications

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“…The similarities imply a close or direct relationship between Sp-D and Ig-Hepta. Sp-D has recently been demonstrated to have a domain that recognizes an immunoglobulin motif [28]. We therefore decided to explore the possibility of the ligand-receptor relationship of Sp-D and Ig-Hepta by monitoring their interaction by immunoprecipitation.…”

Section: Resultsmentioning

confidence: 99%

“…The receptors for Sp-D have been identified in macrophages, which are regulators of inflammation and innate immunity, including the calreticulin/CD91 complex, SIRPα, CD14 and toll-like receptors [35]–[37]. Recently, Fournier et al [28] have demonstrated that Sp-D binds to the membrane-proximal Ig domain of SIRPα. This Ig-domain recognition property of Sp-D may also indirectly support the ligand-receptor relationship of Sp-D and Ig-Hepta that has two Ig-like extracellular domains.…”

Section: Discussionmentioning

confidence: 99%

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Lung Surfactant Levels are Regulated by Ig-Hepta/GPR116 by Monitoring Surfactant Protein D

et al. 2013

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Lung surfactant is a complex mixture of lipids and proteins, which is secreted from the alveolar type II epithelial cell and coats the surface of alveoli as a thin layer. It plays a crucial role in the prevention of alveolar collapse through its ability to reduce surface tension. Under normal conditions, surfactant homeostasis is maintained by balancing its release and the uptake by the type II cell for recycling and the internalization by alveolar macrophages for degradation. Little is known about how the surfactant pool is monitored and regulated. Here we show, by an analysis of gene-targeted mice exhibiting massive accumulation of surfactant, that Ig-Hepta/GPR116, an orphan receptor, is expressed on the type II cell and sensing the amount of surfactant by monitoring one of its protein components, surfactant protein D, and its deletion results in a pulmonary alveolar proteinosis and emphysema-like pathology. By a coexpression experiment with Sp-D and the extracellular region of Ig-Hepta/GPR116 followed by immunoprecipitation, we identified Sp-D as the ligand of Ig-Hepta/GPR116. Analyses of surfactant metabolism in Ig-Hepta+/+ and Ig-Hepta−/− mice by using radioactive tracers indicated that the Ig-Hepta/GPR116 signaling system exerts attenuating effects on (i) balanced synthesis of surfactant lipids and proteins and (ii) surfactant secretion, and (iii) a stimulating effect on recycling (uptake) in response to elevated levels of Sp-D in alveolar space.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Lung Surfactant Levels are Regulated by Ig-Hepta/GPR116 by Monitoring Surfactant Protein D

et al. 2013

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“…Thrombospondin and surfactant have both been shown to bind SIRP␣ (27). Surfactant D in particular has been shown to bind the region near the juxtamembrane region and inhibit phagocytosis and therefore is an especially attractive target (37)(38)(39).…”

Section: Discussionmentioning

confidence: 99%

Cleavage of Signal Regulatory Protein α (SIRPα) Enhances Inflammatory Signaling

Londino

Gulick

Isenberg

et al. 2015

Journal of Biological Chemistry

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Signal regulatory protein ␣ (SIRP␣) is a membrane glycoprotein immunoreceptor abundant in cells of monocyte lineage. SIRP␣ ligation by a broadly expressed transmembrane protein, CD47, results in phosphorylation of the cytoplasmic immunoreceptor tyrosine-based inhibitory motifs, resulting in the inhibition of NF-B signaling in macrophages. Here we observed that proteolysis of SIRP␣ during inflammation is regulated by a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10), resulting in the generation of a membrane-associated cleavage fragment in both THP-1 monocytes and human lung epithelia. We mapped a charge-dependent putative cleavage site near the membrane-proximal domain necessary for ADAM10-mediated cleavage. In addition, a secondary proteolytic cleavage within the membrane-associated SIRP␣ fragment by ␥-secretase was identified. Ectopic expression of a SIRP␣ mutant plasmid encoding a proteolytically resistant form in HeLa cells inhibited activation of the NF-B pathway and suppressed STAT1 phosphorylation in response to TNF␣ to a greater extent than expression of wild-type SIRP␣. Conversely, overexpression of plasmids encoding the proteolytically cleaved SIRP␣ fragments in cells resulted in enhanced STAT-1 and NF-B pathway activation. Thus, the data suggest that combinatorial actions of ADAM10 and ␥-secretase on SIRP␣ cleavage promote inflammatory signaling.Inhibitory receptors including signal regulatory protein ␣ (SIRP␣), 2 CD33, SIGLECs (sialic acid-binding immunoglobulin-type lectins), CD66a, PD-1, CD31, PILRa (paired immunoglobin-like type 2 receptor ␣), CMRF35H, gp49B1, PECAM1, and others have been demonstrated to suppress the initiation of inflammatory signaling and contribute to the resolution of inflammation after infection (1, 2). SIRP␣ is membrane glycoprotein immunoreceptor that is expressed mainly in myeloid and neuronal cells (3). Ligation of SIRP␣ results in phosphorylation of the cytoplasmic immunoreceptor tyrosine-based inhibitory motifs (ITIMs), which recruit and activate SH2 domain-containing phosphotyrosine phosphatases SHP-1 and SHP-2 (4). SIRP␣ signaling results in reduced macrophage migration and phagocytosis and inhibition of NF-B signaling with reduction of release of NF-B-dependent cytokines in macrophages (5, 6). Phosphorylation of SIRP␣ ITIM domains also enhances JAK/STAT activation and NADPH oxidase expression and activity (7). Thus, SIRP␣ serves as an important modulator of the host adaptive immune response. Proteolysis and release of the SIRP␣ NH 2 -terminal domain has been demonstrated in primary cultured neurons, melanoma cells, and macrophage cell lines. Cleavage of murine SIRP␣ through an MMP inhibitor-sensitive pathway was first observed in cultured cells engineered to express both SIRP␣ and an active form of Ras (8). In these cells, blocking SIRP␣ proteolysis resulted in inhibited cell migration, cell spreading, and cytoskeletal reorganization. In addition, SIRP␣ was shown to regulate synaptic activity through activation of MMP inhibitor-sensitive prote...

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“…On the other hand, the binding of Sp-D to SIRPα transmits the immune suppression signals, resulting in decreased cytokine production (Gardai et al, 2003). Interestingly, the SIRPα binding to SP-D was competed with lipopolysaccharide (LPS; Fournier et al, 2012). These observations indicated that the anti-inflammation signals through SIRPα are present in the absence of pathogens, and once pathogens are present, Sp-D binds preferably to LPS or other bacterial carbohydrates, and then induces the host innate immunity.…”

Section: Signal Regulatory Proteinsmentioning

confidence: 99%

Molecular Recognition of Paired Receptors in the Immune System

Kuroki¹,

Furukawa²,

Maenaka³

2012

Front. Microbio.

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Cell surface receptors are responsible for regulating cellular function on the front line, the cell membrane. Interestingly, accumulating evidence clearly reveals that the members of cell surface receptor families have very similar extracellular ligand-binding regions but opposite signaling systems, either inhibitory or stimulatory. These receptors are designated as paired receptors. Paired receptors often recognize not only physiological ligands but also non-self ligands, such as viral and bacterial products, to fight infections. In this review, we introduce several representative examples of paired receptors, focusing on two major structural superfamilies, the immunoglobulin-like and the C-type lectin-like receptors, and explain how these receptors distinguish self and non-self ligands to maintain homeostasis in the immune system. We further discuss the evolutionary aspects of these receptors as well as the potential drug targets for regulating diseases.

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Surfactant Protein D (Sp-D) Binds to Membrane-proximal Domain (D3) of Signal Regulatory Protein α (SIRPα), a Site Distant from Binding Domain of CD47, while Also Binding to Analogous Region on Signal Regulatory Protein β (SIRPβ)

Cited by 21 publications

References 47 publications

Lung Surfactant Levels are Regulated by Ig-Hepta/GPR116 by Monitoring Surfactant Protein D

Lung Surfactant Levels are Regulated by Ig-Hepta/GPR116 by Monitoring Surfactant Protein D

Cleavage of Signal Regulatory Protein α (SIRPα) Enhances Inflammatory Signaling

Molecular Recognition of Paired Receptors in the Immune System

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