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

2009 ◽  
Vol 284 (24) ◽  
pp. 16667-16678 ◽  
Author(s):  
Adam Kotorashvili ◽  
Scott J. Russo ◽  
Surafel Mulugeta ◽  
Susan Guttentag ◽  
Michael F. Beers
Keyword(s):  
Protein C ◽  
Surfactant Protein ◽  
Proteolytic Processing ◽  
Alveolar Type ◽  
Phase Array ◽  
Ww Domains ◽  
E3 Ligases ◽  
Surfactant Protein C ◽  
Human Type

Biosynthesis of surfactant protein C (SP-C) by alveolar type 2 cells requires proteolytic processing of a 21-kDa propeptide (proSP-C21) 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-C21 to distal processing organelles is dependent upon the NH2-terminal cytoplasmic SP-C propeptide, which contains a conserved PPDY motif. In A549 cells, transfection of EGFP/proSP-C21 constructs containing polyalanine substitution for Glu11–Thr18, 13PPDY16, or 14P,16Y 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 NH2 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 35S-labeled proSP-C21. Mutagenesis of potential acceptor sites for ubiquitination in the cytosolic domain of proSP-C (Lys6, Lys34, or both) failed to inhibit trafficking of EGFP/proSP-C21. These results indicate that PPDY-mediated 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.

Autophagy regulates hyperoxia-induced intracellular accumulation of surfactant protein C in alveolar type II cells

2015 ◽  
Vol 408 (1-2) ◽  
pp. 181-189 ◽  
Author(s):  
Liang Zhang ◽  
Shuang Zhao ◽  
Li-Jie Yuan ◽  
Hong-Min Wu ◽  
Hong Jiang ◽  
...  
Keyword(s):  
Protein C ◽  
Surfactant Protein ◽  
Alveolar Type ◽  
Type Ii Cells ◽  
Type Ii ◽  
Intracellular Accumulation ◽  
Alveolar Type Ii Cells ◽  
Surfactant Protein C

scholarly journals Surfactant protein C mutation links postnatal type 2 cell dysfunction to adult disease

JCI Insight ◽  
2021 ◽  
Author(s):  
Sneha Sitaraman ◽  
Emily P. Martin ◽  
Cheng-Lun Na ◽  
Shuyang Zhao ◽  
Jenna Green ◽  
...  
Keyword(s):  
Protein C ◽  
Surfactant Protein ◽  
Adult Disease ◽  
Surfactant Protein C ◽  
Cell Dysfunction

scholarly journals Role of CCR2+ Myeloid Cells in Inflammation Responses Driven by Expression of a Surfactant Protein-C Mutant in the Alveolar Epithelium

2021 ◽  
Vol 12 ◽  
Author(s):  
Alessandro Venosa ◽  
Sophie Cowman ◽  
Jeremy Katzen ◽  
Yaniv Tomer ◽  
Brittnie S. Armstrong ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Mrna Expression ◽  
Protein C ◽  
Cell Activation ◽  
Surfactant Protein ◽  
Chronic Obstructive ◽  
Alveolar Type ◽  
Genetic Ablation ◽  
Surfactant Protein C

Acute inflammatory exacerbations (AIE) represent precipitous deteriorations of a number of chronic lung conditions, including pulmonary fibrosis (PF), chronic obstructive pulmonary disease and asthma. AIEs are marked by diffuse and persistent polycellular alveolitis that profoundly accelerate lung function decline and mortality. In particular, excess monocyte mobilization during AIE and their persistence in the lung have been linked to poor disease outcome. The etiology of AIEs remains quite uncertain, but environmental exposure and genetic predisposition/mutations have been identified as two contributing factors. Guided by clinical evidence, we have developed a mutant model of pulmonary fibrosis leveraging the PF-linked missense isoleucine to threonine substitution at position 73 [I73T] in the alveolar type-2 cell-restricted Surfactant Protein-C [SP-C] gene [SFTPC]. With this toolbox at hand, the present work investigates the role of peripheral monocytes during the initiation and progression of AIE-PF. Genetic ablation of CCR2+ monocytes (SP-CI73TCCR2KO) resulted in improved lung histology, mouse survival, and reduced inflammation compared to SP-CI73TCCR2WT cohorts. FACS analysis of CD11b+CD64-Ly6Chi monocytes isolated 3 d and 14 d after SP-CI73T induced injury reveals dynamic transcriptional changes associated with “Innate Immunity’ and ‘Extracellular Matrix Organization’ signaling. While immunohistochemical and in situ hybridization analysis revealed comparable levels of tgfb1 mRNA expression localized primarily in parenchymal cells found nearby foci of injury we found reduced effector cell activation (C1q, iNOS, Arg1) in SP-CI73TCCR2KO lungs as well as partial colocalization of tgfb1 mRNA expression in Arg1+ cells. These results provide a detailed picture of the role of resident macrophages and recruited monocytes in the context of AIE-PF driven by alveolar epithelial dysfunction.

Localization of Misprocessed Pulmonary Surfactant Protein C in Tubular Myelin Enriched Fractions By Cryo Immunogold Labeling

2000 ◽  
Vol 6 (S2) ◽  
pp. 868-869
Author(s):  
C.-L. Na ◽  
E. A. Evans ◽  
H. T. Akinbi ◽  
T. E. Weaver
Keyword(s):  
Pulmonary Surfactant ◽  
Protein C ◽  
Intracellular Localization ◽  
Surfactant Protein ◽  
Biologically Active ◽  
Alveolar Type ◽  
Double Knockout ◽  
Surfactant Protein C ◽  
Associated Proteins ◽  
Pulmonary Surfactant Protein

Pulmonary surfactant is secreted by alveolar type II cells and reduces the surface tension at the air-liquid interface of alveoli. After pulmonary surfactant is secreted into the alveolar space, it transforms into tubular myelin, a highly ordered 3-dimensional lattice-like structure. Pulmonary surfactant protein C (SP-C), one of four pulmonary surfactant associated proteins, is synthesized as a proprotein which is processed to biologically active 35 amino acid mature peptide by proteolytic cleavage of N- and C-terminal peptides from the SP-C propeptide (Weaver, 1998). Processing of SP-C is linked to the expression of pulmonary surfactant protein B (SP-B): In SP-B deficient mice, SP-C is misprocessed and present in the bronchoalveolar lavage (BAL; Vorbroker et. al., 1995a). Although the intracellular localization of SP-C is well established (Vorbroker et. al., 1995b), there is no ultrastructure study available regarding the localization of misprocessed SP-C in the airway. In this study, we used transgenic mice expressing a truncated human SP-B propeptide (hSP-BΔC+/+) bred into the murine granulocyte macrophage colony stimulating factor (GMCSF) and SP-B double knockout background (hSP-BΔC+/+: GMCSF-/-: mSP-B-/-) as a model to localize the misprocessed SP-C by cryoimmunogold labeling.

Rabbit surfactant protein C: cDNA cloning and regulation of alternatively spliced surfactant protein C mRNAs

1993 ◽  
Vol 264 (2) ◽  
pp. 1-1
Author(s):  
Vijayakumar Boggaram ◽  
Ramgopal K. Margana
Keyword(s):  
Cdna Cloning ◽  
Genomic Dna ◽  
Protein C ◽  
Surfactant Protein ◽  
Proteolytic Processing ◽  
Carboxy Terminus ◽  
Left Hand ◽  
Surfactant Protein C ◽  
Hand Column ◽  
Alternatively Spliced

Pages L634–L644: Vijayakumar Boggaram and Ramgopal K. Margana. “Rabbit surfactant protein C: cDNA cloning and regulation of alternatively spliced surfactant protein C mRNAs.” Page L634, left-hand column, in the abstract, the sentence beginning on line 22 should read: Southern hybridization analysis of genomic DNA suggested that SP-C mRNAs are encoded by a single gene. Polymerase chain reaction-amplification of genomic DNA with oligonucleotide primers flanking the insertional sequence and sequence analysis of amplified DNA showed that SP-C mRNAs are produced by alternative use of 3' splice sites of intron 5 of SP-C gene. Page L634, left-hand column, paragraph 2, line 4 should read: SP-A [relative molecular weight (Mr) ≈35,000] and SP-D (Mr≈43,000) are hydrophilic proteins that are similar in having collagenous amino-terminus domain and noncollagenous lectinlike carboxy-terminus domain. SP-B (Mr ap8,000) and SP-C (Mr ap5,000) are hydrophobic proteins derived from larger precursor proteins by amino- and carboxy-terminus proteolytic processing.

scholarly journals Surfactant Protein C Interacts with WW Domains of Nedd 4 Via an N‐terminal PPDY Motif

2007 ◽  
Vol 21 (5) ◽  
Author(s):  
Adam Kotorashvili ◽  
Surafel Mulugeta ◽  
Scott J. Russo ◽  
Michael F. Beers
Keyword(s):  
Protein C ◽  
Surfactant Protein ◽  
Ww Domains ◽  
Surfactant Protein C
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