Lack of evidence for a role of anthrax toxin receptors as surface receptors for collagen VI and for its cleaved-off C5 domain/endotrophin

Przyklenk, Matthias; Heumüller, Stefanie Elisabeth; Freiburg, Carolin D.; Lütke, Steffen; Sengle, Gerhard; Koch, Manuel; Paulsson, Mats; Schiavinato, Alvise; Wagener, Raimund

doi:10.1016/j.isci.2022.105116

Cited by 8 publications

(4 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The major finding of this study is the mediating role of endotrophin in the effect of obesity on CAD in humans. Previous studies reported endotrophin as an important hormone that induces metabolic dysfunction, fibrosis, and inflammation in rodent models [40][41][42]57 , and cross-sectional studies in humans have found that increased circulating endotrophin level was observationally associated with cardiovascular events and all-cause mortality [43][44][45]58 . However, cross-sectional observational studies cannot disentangle cause and consequence.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

COL6A3-derived endotrophin mediates the effect of obesity on coronary artery disease: an integrative proteogenomics analysis

Yoshiji

Butler‐Laporte

et al. 2023

Preprint

View full text Add to dashboard Cite

Obesity strongly increases the risk of cardiometabolic diseases, yet the underlying mediators of this relationship are not fully understood. Given that obesity has broad effects on circulating protein levels, we investigated circulating proteins that mediate the effects of obesity on coronary artery disease (CAD), stroke, and type 2 diabetes—since doing so may prioritize targets for therapeutic intervention. By integrating proteome-wide Mendelian randomization (MR) screening 4,907 plasma proteins, colocalization, and mediation analyses, we identified seven plasma proteins, including collagen type VI α3 (COL6A3). COL6A3 was strongly increased by body mass index (BMI) (β = 0.32, 95% CI: 0.26–0.38, P = 3.7 × 10-8per s.d. increase in BMI) and increased the risk of CAD (OR = 1.47, 95% CI:1.26–1.70, P = 4.5 × 10-7per s.d. increase in COL6A3). Notably, COL6A3 is cleaved at its C-terminus to produce endotrophin, which was found to mediate this effect on CAD. In single-cell RNA sequencing of adipose tissues and coronary arteries, COL6A3 was highly expressed in cell types involved in metabolic dysfunction and fibrosis. Finally, we found that body fat reduction can reduce plasma levels of COL6A3-derived endotrophin, thereby highlighting a tractable way to modify endotrophin levels. In summary, we provide actionable insights into how circulating proteins mediate the effect of obesity on cardiometabolic diseases and prioritize endotrophin as a potential therapeutic target.

show abstract

Section: Discussionmentioning

confidence: 99%

“…Endotrophin is produced in multiple tissues, including adipose tissue 40,41 . Endotrophin strongly induces fibrosis and inflammation, and recent evidence suggests that it is involved in obesity-induced metabolic dysfunction [40][41][42][43][44][45] (Fig 4a).…”

Section: Identification Of the Causal Domain Of Col6a3mentioning

confidence: 99%

COL6A3-derived endotrophin mediates the effect of obesity on coronary artery disease: an integrative proteogenomics analysis

Yoshiji

Butler‐Laporte

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…While the role of ANTXR1 in anthrax poisoning is well-established, its physiological functions are still not fully understood. Like integrin VWA domains, the VWA domain of ANTXR1 has been found to mediate protein–protein interactions with the extracellular matrix (ECM), although there is uncertainty regarding the specific ECM components that bind to the receptor 8 , 11 . Additionally, ANTXR1 interacts with the cytoskeleton via its cytoplasmic tail, potentially by binding directly to actin 10 , 12 .…”

Section: Introductionmentioning

confidence: 99%

ANTXR1 deficiency promotes fibroblast senescence: implications for GAPO syndrome as a progeroid disorder

Przyklenk,

Karmacharya,

Bonasera

et al. 2024

Sci Rep

Self Cite

View full text Add to dashboard Cite

ANTXR1 is one of two cell surface receptors mediating the uptake of the anthrax toxin into cells. Despite substantial research on its role in anthrax poisoning and a proposed function as a collagen receptor, ANTXR1’s physiological functions remain largely undefined. Pathogenic variants in ANTXR1 lead to the rare GAPO syndrome, named for its four primary features: Growth retardation, Alopecia, Pseudoanodontia, and Optic atrophy. The disease is also associated with a complex range of other phenotypes impacting the cardiovascular, skeletal, pulmonary and nervous systems. Aberrant accumulation of extracellular matrix components and fibrosis are considered to be crucial components in the pathogenesis of GAPO syndrome, contributing to the shortened life expectancy of affected individuals. Nonetheless, the specific mechanisms connecting ANTXR1 deficiency to the clinical manifestations of GAPO syndrome are largely unexplored. In this study, we present evidence that ANTXR1 deficiency initiates a senescent phenotype in human fibroblasts, correlating with defects in nuclear architecture and actin dynamics. We provide novel insights into ANTXR1's physiological functions and propose GAPO syndrome to be reconsidered as a progeroid disorder highlighting an unexpected role for an integrin-like extracellular matrix receptor in human aging.

show abstract

“…Cells were selected with puromycin (1 μg/ml), and the recombinant proteins purified directly from serum-free culture medium. For the generation of stable WI-26 VA4 cell lines, the PCR products were cloned into a modified sleeping beauty vector [40,41] was added to the cells every second day.…”

Section: Introductionmentioning

confidence: 99%

The UCMD-Causing COL6A1 ( $c . 930 + 189 C > T$ ) Intron Mutation Leads to the Secretion and Aggregation of Single Mutated Collagen VI α1 Chains

Freiburg,

Solomon-Degefa,

Freiburg

et al. 2023

Human Mutation

Self Cite

View full text Add to dashboard Cite

Collagen VI is a unique member of the collagen family. Its assembly is a complex multistep process and the vulnerability of the process is manifested in muscular diseases. Mutations in COL6A1, COL6A2, and COL6A3 lead to the severe Ullrich Congenital Muscular Dystrophy (UCMD) and a spectrum of disease of varying severity including the milder Bethlem muscular dystrophy. The recently identified dominant intronic mutation in COL6A1 ( c . 930 + 189 C > T ) leads to the partial in-frame insertion of a pseudoexon between exon 11 and exon 12. The pseudoexon is translated into 24 amino acid residues in the N-terminal region of the triple helix and results in the interruption of the typical G-X-Y motif. This recurrent de novo mutation leads to UCMD with a severe progression within the first decade of life. Here, we demonstrate that a mutation-specific antibody detects the mutant chain colocalizing with wild type collagen VI in the endomysium in patient muscle. Surprisingly, in the cell culture of patient dermal fibroblasts, the mutant chain is secreted as a single α chain, while in parallel, normal collagen VI tetramers are assembled with the wild-type α1 chain. The mutant chain cannot be incorporated into collagen VI tetramers but forms large aggregates in the extracellular matrix that may retain the ability to interact with collagen VI and potentially with other molecules. Also, α1 chain-deficient WI-26 VA4 cells transfected with the mutant α1 chain do not assemble collagen VI tetramers but, instead, form aggregates. Interestingly, both the wild type and the mutant single α1 chains form amorphous aggregates when expressed in HEK293 cells in the absence of α2 and α3 chains. The detection of aggregated, assembly incompetent, mutant collagen VI α1 chains provides novel insights into the disease pathophysiology of UCMD patients with the COL6A1 ( c . 930 + 189 C > T ) mutation.

show abstract

Lack of evidence for a role of anthrax toxin receptors as surface receptors for collagen VI and for its cleaved-off C5 domain/endotrophin

Cited by 8 publications

References 53 publications

COL6A3-derived endotrophin mediates the effect of obesity on coronary artery disease: an integrative proteogenomics analysis

COL6A3-derived endotrophin mediates the effect of obesity on coronary artery disease: an integrative proteogenomics analysis

ANTXR1 deficiency promotes fibroblast senescence: implications for GAPO syndrome as a progeroid disorder

The UCMD-Causing COL6A1 ( $c . 930 + 189 C > T$ ) Intron Mutation Leads to the Secretion and Aggregation of Single Mutated Collagen VI α1 Chains

Contact Info

Product

Resources

About

Lack of evidence for a role of anthrax toxin receptors as surface receptors for collagen VI and for its cleaved-off C5 domain/endotrophin

Cited by 8 publications

References 53 publications

COL6A3-derived endotrophin mediates the effect of obesity on coronary artery disease: an integrative proteogenomics analysis

COL6A3-derived endotrophin mediates the effect of obesity on coronary artery disease: an integrative proteogenomics analysis

ANTXR1 deficiency promotes fibroblast senescence: implications for GAPO syndrome as a progeroid disorder

The UCMD-Causing COL6A1 ( c . 930 + 189 C > T ) Intron Mutation Leads to the Secretion and Aggregation of Single Mutated Collagen VI α1 Chains

Contact Info

Product

Resources

About

The UCMD-Causing COL6A1 ( $c . 930 + 189 C > T$ ) Intron Mutation Leads to the Secretion and Aggregation of Single Mutated Collagen VI α1 Chains