Interstitial lung disease in a baby with a de novo mutation in the SFTPC gene

Brasch, Frank; Griese, Matthias; Tredano, M; Johnen, Georg; Ochs, Matthias; Rieger, Christian; Mulugeta, Surafel; Müller, Klaus; Bahuau, Michel; Beers, Michael F.

doi:10.1183/09031936.04.00000104

Cited by 141 publications

(145 citation statements)

References 48 publications

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“…Mutations in the SFTPC gene that are associated with ILD are found in three different regions of proSP-C. First, a majority of the mutations are found within the Brichos domain and these appear to lead to a more severe phenotype, with decreased or no mature SP-C and formation of cytotoxic protein aggregates [11]. Second, mutations localised in the region between the Brichos domain and the transmembrane domain are mainly associated with altered intracellular trafficking [18]. Third, one mutation has been found in the mature peptide and the phenotype associated with it has not been well characterised, but ER retention has been suggested [11].…”

Section: Discussionmentioning

confidence: 99%

Mutations linked to interstitial lung disease can abrogate anti-amyloid function of prosurfactant protein C

Nerelius

Martin

Peng

et al. 2008

Biochemical Journal

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International audienceThe newly synthesized surfactant protein C precursor (proSP-C) is an integral endoplasmic reticulum (ER) membrane protein with a single metastable polyVal α-helical transmembrane domain that comprises two thirds of the mature peptide. More than 20 mutations in the ER-lumenal, C-terminal domain of proSP-C (CTC), are associated with interstitial lung disease (ILD), and some of the mutations cause intracellular accumulation of cytotoxic protein aggregates and a corresponding decrease in mature SP-C. Here it is shown that (i) human embryonic kidney cells expressing the ILD associated mutants proSP-CL188Q and proSP-CΔExon4 accumulate Congo red positive amyloid-like inclusions, while cells transfected with the mutant proSP-CI73T do not, (ii) transfection of CTC into cells expressing proSP-CL188Q results in a stable CTC/proSP-CL188Q complex, increased proSP-CL188Q half life and reduced formation of Congo red positive deposits, (iii) replacement of the metastable polyVal transmembrane segment with a stable polyLeu likewise prevents formation of amyloid-like proSP-CL188Q aggregates, and (iv) binding of recombinant CTC to non-helical SP-C blocks SP-C amyloid fibril formation. These data suggest that CTC can prevent the polyVal segment of proSP-C from promoting formation of amyloid-like deposits during biosynthesis, by binding to non-helical conformations. Mutations in the Brichos domain of proSP-C may lead to ILD via loss of CTC chaperone function

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Section: Discussionmentioning

confidence: 99%

Mutations linked to interstitial lung disease can abrogate anti-amyloid function of prosurfactant protein C

Nerelius

Martin

Peng

et al. 2008

Biochemical Journal

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“…The first and largest category involves mutations in a region of the proSP-C termed BRICHOS which is associated with gross protein misfolding, aggregation, induction of endoplasmic reticulum stress, and promotion of apoptosis and generation of proinflammatory cytokines (52). The second category of proSP-C mutations are also associated with the development of interstitial lung disease but are characterized by accumulation of mutant protein in endosomes and lysosomes (53,54). The third set of mutations in the proSP-C NTP results in retention in the ER (55).…”

Section: Discussionmentioning

confidence: 99%

Anterograde Transport of Surfactant Protein C Proprotein to Distal Processing Compartments Requires PPDY-mediated Association with Nedd4 Ubiquitin Ligases

Kotorashvili

Russo

Mulugeta

et al. 2009

Journal of Biological Chemistry

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Biosynthesis of surfactant protein C (SP-C) by alveolar type 2 cells requires proteolytic processing of a 21-kDa propeptide (proSP-C 21 ) in post-Golgi compartments to yield a 3.7-kDa mature form. Scanning alanine mutagenesis, binding assays, and co-immunoprecipitation were used to characterize the proSP-C targeting domain. Delivery of proSP-C 21 to distal processing organelles is dependent upon the NH 2 -terminal cytoplasmic SP-C propeptide, which contains a conserved PPDY motif. In A549 cells, transfection of EGFP/proSP-C 21 constructs containing polyalanine substitution for Glu 11 -Thr 18 , 13 PPDY 16 , or 14 P, 16 Y produced endoplasmic reticulum retention of the fusion proteins. Protein-protein interactions of proSP-C with known WW domains were screened using a solid-phase array that revealed binding of the proSP-C NH 2 terminus to several WW domains found in the Nedd4 family of E3 ligases. Specificity of the interaction was confirmed by co-immunoprecipitation of proSP-C and Nedd4 or Nedd4-2 in epithelial cell lines. By Western blotting and reverse transcription-PCR, both forms were detected in primary human type 2 cells. Knockdown of Nedd4-2 by small interference RNA transfection of cultured human type 2 cells blocked processing of 35 S-labeled proSP-C 21. Mutagenesis of potential acceptor sites for ubiquitination in the cytosolic domain of proSP-C (Lys 6 , Lys 34 , or both) failed to inhibit trafficking of EGFP/proSP-C 21 . These results indicate that PPDYmediated interaction with Nedd4 E3-ligases is required for trafficking of proSP-C. We speculate that the Nedd4/proSP-C tandem is part of a larger protein complex containing a ubiquitinated component that further directs its transport. Surfactant protein C (SP-C)3 is a hydrophobic lung-specific protein that co-isolates with the biophysically active phospholipid fraction of pulmonary surfactant (1). The 3.7-kDa alveolar form of SP-C (SP-C 3.7 or mature SP-C) is a 35-amino acid, valine-rich peptide that results from synthesis of a 197 amino acid precursor form (proSP-C 21 ). Within the endoplasmic reticulum (ER), proSP-C 21 exists as a type II bitopic transmembrane protein (N cyt /C lumen ), which remains integrally membrane-associated while it is extensively processed by four post-translational endoproteolytic cleavages that take place in post-Golgi compartments (2-6). The resulting mature protein is transferred into the lumen of lamellar bodies for secretion into the alveolar space together with surfactant phospholipid and SP-B (7). Thus, the complete biosynthesis of SP-C 3.7 is critically dependent upon oligomeric sorting and targeting of proSP-C 21 to subcellular processing compartments distal to the ER/Golgi.Using deletional mutagenesis, we had previously shown that the NH 2 -terminal propeptide flanking domain (NTP) of proSP-C, which is oriented into the cytosol, contained potential targeting motifs for post-Golgi trafficking (8, 9). The candidate region included the amino acid sequence Met 10 -Thr 18 and, when present, was sufficient to direct transf...

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“…The exchange of glutamine for leucine at position 188 gives abnormal-appearing lamellar bodies, slowed cell growth, and signs of cytotoxicity (14). Expression of proSP-C with mutations in positions 66 or 73 (E66K and I73T) give rise to detectable amounts of mature SP-C (15,16). Thus it appears that the effect on proSP-C processing depends on where the mutation is located in the proprotein.…”

mentioning

confidence: 98%

The Brichos Domain-containing C-terminal Part of Pro-surfactant Protein C Binds to an Unfolded Poly-Val Transmembrane Segment

Johansson

Nordling

Weaver

et al. 2006

Journal of Biological Chemistry

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Native lung surfactant protein C (SP-C) is a 4.2-kDa acylpeptide that associates with alveolar surfactant phospholipids via a transmembrane ␣-helix. This helix contains mainly Val, although poly-Val is inefficient in helix formation, and helical SP-C can spontaneously convert to ␤-sheet aggregates and amyloid-like fibrils. SP-C is cleaved out from a 21-kDa integral membrane protein, proSP-C, in the alveolar type II cell. Recently several mutations localized in the endoplasmic reticulum-lumenal (C-terminal) part of proSP-C (CTproSP-C) have been associated with intracellular accumulation of toxic forms of proSP-C, low levels of mature SP-C, and development of interstitial lung disease. CTproSP-C contains a ϳ100-residue Brichos domain of unknown function that is also found in other membrane proteins associated with amyloid formation, dementia, and cancer. Here we find that recombinant CTproSP-C binds lipid-associated SP-C, which is in ␤-strand conformation, and that this interaction results in an increased helical content. In contrast, CTproSP-C does not bind ␣-helical SP-C. Recombinant CTproSP-C(L188Q), a mutation associated with interstitial lung disease, shows secondary and quaternary structures similar to those of wild type CTproSP-C but is unable to bind lipid-associated ␤-strand SP-C. Transfection of CTproSP-C into HEK293 cells that express proSP-C(L188Q) increases the amount of proSP-C protein, whereas no effect is seen on cells expressing wild type proSP-C. These findings suggest that CTproSP-C binds nonhelical SP-C and thereby prevents ␤-sheet aggregation and that mutations in CTproSP-C can interfere with this function.

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Interstitial lung disease in a baby with a de novo mutation in the SFTPC gene

Cited by 141 publications

References 48 publications

Mutations linked to interstitial lung disease can abrogate anti-amyloid function of prosurfactant protein C

Mutations linked to interstitial lung disease can abrogate anti-amyloid function of prosurfactant protein C

Anterograde Transport of Surfactant Protein C Proprotein to Distal Processing Compartments Requires PPDY-mediated Association with Nedd4 Ubiquitin Ligases

The Brichos Domain-containing C-terminal Part of Pro-surfactant Protein C Binds to an Unfolded Poly-Val Transmembrane Segment

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