Connective tissue alterations in Fkbp10−/− mice

Lietman, Caressa; Rajagopal, Abbhirami; Homan, Erica P.; Munivez, Elda; Jiang, Ming; Bertin, Terry; Chen, Yuqing; Hicks, John; Weis, MaryAnn; Eyre, David R.; Lee, Brendan; Krakow, Deborah

doi:10.1093/hmg/ddu197

Cited by 57 publications

(59 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…No colocalization was observed with the Golgi-specific protein GOLGA1 (29), indicating that FKBP10 is not associated with transport processes across the trans-Golgi network to the extracellular space. This suggests that FKBP10 mainly functions as an ER-resident chaperone and/or foldase in phLF, which agrees with previous studies in chondroblasts and embryonic fibroblasts (19,27). As there is evidence that ER stress contributes to IPF pathology (30, 31), we assessed whether FKBP10 is induced by ER .…”

Section: Discussionsupporting

confidence: 92%

“…Mutations in FKBP10 lead to collagen-related disorders such as osteogenesis imperfecta, and studies in the last 4 years have suggested an association of these mutations with attenuated collagen secretion and diminished collagen I cross-linking in dermal fibroblasts and bone (15)(16)(17)(18). A recent study showed that Fkbp10 2/2 mouse embryos are postnatally lethal and display reduced collagen cross-linking in calvarial bone (19).…”

mentioning

confidence: 99%

See 1 more Smart Citation

FK506-Binding Protein 10, a Potential Novel Drug Target for Idiopathic Pulmonary Fibrosis

Staab-Weijnitz

Fernandez

Knüppel

et al. 2015

Am J Respir Crit Care Med

View full text Add to dashboard Cite

Rationale: Increased abundance and stiffness of the extracellular matrix, in particular collagens, is a hallmark of idiopathic pulmonary fibrosis (IPF). FK506-binding protein 10 (FKBP10) is a collagen chaperone, mutations of which have been indicated in the reduction of extracellular matrix stiffness (e.g., in osteogenesis imperfecta).Objectives: To assess the expression and function of FKBP10 in IPF. Methods:We assessed FKBP10 expression in bleomycininduced lung fibrosis (using quantitative reverse transcriptase-polymerase chain reaction, Western blot, and immunofluorescence), analyzed microarray data from 99 patients with IPF and 43 control subjects from a U.S. cohort, and performed Western blot analysis from 6 patients with IPF and 5 control subjects from a German cohort. Subcellular localization of FKBP10 was assessed by immunofluorescent stainings. The expression and function of FKBP10, as well as its regulation by endoplasmic reticulum stress or transforming growth factor-b 1 , was analyzed by small interfering RNA-mediated loss-of-function experiments, quantitative reverse transcriptase-polymerase chain reaction, Western blot, and quantification of secreted collagens in the lung and in primary human lung fibroblasts (phLF). Effects on collagen secretion were compared with those of the drugs nintedanib and pirfenidone, recently approved for IPF.Measurements and Main Results: FKBP10 expression was up-regulated in bleomycin-induced lung fibrosis and IPF. Immunofluorescent stainings demonstrated localization to interstitial (myo)fibroblasts and CD68 1 macrophages. Transforming growth factor-b 1 , but not endoplasmic reticulum stress, induced FKBP10 expression in phLF. The small interfering RNA-mediated knockdown of FKBP10 attenuated expression of profibrotic mediators and effectors, including collagens I and V and a-smooth muscle actin, on the transcript and protein level. Importantly, loss of FKBP10 expression significantly suppressed collagen secretion by phLF.Conclusions: FKBP10 might be a novel drug target for IPF.

show abstract

Section: Discussionsupporting

confidence: 92%

mentioning

confidence: 99%

FK506-Binding Protein 10, a Potential Novel Drug Target for Idiopathic Pulmonary Fibrosis

Staab-Weijnitz

Fernandez

Knüppel

et al. 2015

Am J Respir Crit Care Med

View full text Add to dashboard Cite

show abstract

“…Further studies are required to address the particular details of the interaction between Hsp47 and the SH3 domain of TANGO1. It is interesting to note that null mouse models of Hsp47, FKBP65, Prolyl 3-hydroxylase 1, and cartilage-associated protein show embryonic lethality or disturbances in various tissues (30,(35)(36)(37) and that human mutations in these proteins lead to a phenotype of recessive OI (38).…”

Section: Discussionmentioning

confidence: 99%

Intracellular mechanisms of molecular recognition and sorting for transport of large extracellular matrix molecules

Ishikawa

Ito

Nagata

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

104

118

View full text Add to dashboard Cite

Extracellular matrix (ECM) proteins are biosynthesized in the rough endoplasmic reticulum (rER) and transported via the Golgi apparatus to the extracellular space. The coat protein complex II (COPII) transport vesicles are approximately 60-90 nm in diameter. However, several ECM molecules are much larger, up to several hundreds of nanometers. Therefore, special COPII vesicles are required to coat and transport these molecules. Transmembrane Protein Transport and Golgi Organization 1 (TANGO1) facilitates loading of collagens into special vesicles. The Src homology 3 (SH3) domain of TANGO1 was proposed to recognize collagen molecules, but how the SH3 domain recognizes various types of collagen is not understood. Moreover, how are large noncollagenous ECM molecules transported from the rER to the Golgi? Here we identify heat shock protein (Hsp) 47 as a guide molecule directing collagens to special vesicles by interacting with the SH3 domain of TANGO1. We also consider whether the collagen secretory model applies to other large ECM molecules.E xtracellular matrix (ECM) proteins are the most abundant proteins in our body. They build the body architecture and help to maintain tissue homeostasis in bone, skin, cartilage, and tendon (1). They are biosynthesized in the rough endoplasmic reticulum (ER; rER) and traverse the Golgi apparatus en route to the extracellular space. A transport vesicle for cargo exists to traffic molecules from the rER into the extracellular space. This secretory vesicle is called a coat protein complex II (COPII) vesicle (2-4). It is generated at the ER exit site and usually has a diameter of 60-90 nm. This carrier can transport many secreted proteins. However, larger or elongated molecules, especially collagens and other ECM molecules, will not fit into such small vesicles.There are more than 20 different collagen types in humans (5, 6). Type I, II, III, and V collagens are classified as fibrillar collagens, which are the most abundant. Type IV collagen is an important structural element in basement membranes. Type VII collagen forms anchoring fibrils at the epidermal-dermal junction in skin. These collagens are all more than 300 nm long. In addition to its elongated triple helical structure, type VII collagen has a 140-kDa noncollagenous domain at the amino terminus. Although more flexible than collagens, fibrillin molecules are also elongated, measured to be approximately 150 nm in length (7). For these molecules, special COPII vesicles or other trafficking systems are required for secretion.It has been proposed that procollagen molecules, which are the precursors of collagen, are transferred in COPII vesicles to the Golgi (8-10). In 2009, Transmembrane Protein Transport and Golgi Organization 1 (TANGO1), encoded by MIA3, was shown to facilitate collagens into COPII vesicles at the ER exit site (11). In the cytoplasm, TANGO1 interacts with Sec23A/Sec24C, the outer molecules of COPII vesicles, and cTAGE5, a homolog of TANGO1 that lacks the rER domains of TANGO. These interactions occur via a ...

show abstract

“…They result in loss of prolyl-hydroxylation at Pro-986 (27) and, in CypB knock-out mice, defective lysine hydroxylation in bone (28) and tendon (29) collagens. Furthermore, we know that FKBP65, another peptidyl prolyl isomerase and ER chaperone, can regulate the activity of LH2 the predicted telopeptide lysine hydroxylase (12,30,31).…”

Section: Discussionmentioning

confidence: 99%

P3h3-null and Sc65-null Mice Phenocopy the Collagen Lysine Under-hydroxylation and Cross-linking Abnormality of Ehlers-Danlos Syndrome Type VIA

Hudson

Weis

Rai

et al. 2017

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Edited by Xiao-Fan WangTandem mass spectrometry was applied to tissues from targeted mutant mouse models to explore the collagen substrate specificities of individual members of the prolyl 3-hydroxylase (P3H) gene family. Previous studies revealed that P3h1 preferentially 3-hydroxylates proline at a single site in collagen type I chains, whereas P3h2 is responsible for 3-hydroxylating multiple proline sites in collagen types I, II, IV, and V. In screening for collagen substrate sites for the remaining members of the vertebrate P3H family, P3h3 and Sc65 knock-out mice revealed a common lysine under-hydroxylation effect at helical domain cross-linking sites in skin, bone, tendon, aorta, and cornea. No effect on prolyl 3-hydroxylation was evident on screening the spectrum of known 3-hydroxyproline sites from all major tissue collagen types. However, collagen type I extracted from both The collagen family of proteins has evolved into many different genes and gene translational products each with variably regulated post-translational modifications (1, 2). Even within a single genetic type of collagen, the post-translational quality of the protein is known to be regulated with a high degree of tissue specificity (3, 4). The functional significance of this post-translational variability is still not fully understood, although for fibril-forming collagens the number, placement, and chemistry of covalent intermolecular cross-links seem to be critically important regulators of tissue material properties and function (5-7).In the last decade, new insights on the significance of a relatively rare collagen modification, prolyl 3-hydroxylation, came from the discovery that recessive forms of osteogenesis imperfecta (OI) 2 are caused by biallelic mutations in prolyl 3-hydroxylase 1 (P3H1; Lepre1), CRTAP (Leprel3), or CypB (PPIB) (8). These proteins, which form a P3H1 enzyme complex, act on nascent collagen chains in the ER (9). Mutations in at least 6 further genes that encode either enzymes (e.g. PLOD2 encoding lysyl hydroxylase-2 (LH2) (10)) or chaperones (e.g. FKBP10 encoding FKBP65 (11, 12)), needed for collagen modification, folding, transport, and normal mineralization, have been shown to cause OI variants. We have gained insights on the disease-causing mechanisms by analyzing tissue collagens from OI patients and mouse models of OI. For example, P3H1, CRTAP, and PPIB mutations all cause telopeptide lysine overhydroxylation (5), whereas PLOD2 or FKBP10 mutations cause telopeptide lysine under-hydroxylation (10 -12). A common effect from all these mutations is an altered collagen cross-linking chemistry. These findings suggest an interplay in the ER between the prolyl 3-hydroxylation complex and the lysyl hydroxylation machinery.Human mutations in P3H2 (Leprel1) have been shown to cause the eye disorder high myopia (13-15). Two different P3H2 knock-out mice have so far been generated by separate laboratories, the first was embryonic lethal (16), whereas the second had no obvious phenotype (17). Mass spectral analysis of...

show abstract

Connective tissue alterations in Fkbp10−/− mice

Cited by 57 publications

References 34 publications

FK506-Binding Protein 10, a Potential Novel Drug Target for Idiopathic Pulmonary Fibrosis

FK506-Binding Protein 10, a Potential Novel Drug Target for Idiopathic Pulmonary Fibrosis

Intracellular mechanisms of molecular recognition and sorting for transport of large extracellular matrix molecules

P3h3-null and Sc65-null Mice Phenocopy the Collagen Lysine Under-hydroxylation and Cross-linking Abnormality of Ehlers-Danlos Syndrome Type VIA

Contact Info

Product

Resources

About