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Moonlighting complement inhibitors and their link to human diseases

Ekström, Alexander LU (2025) In Lund University, Faculty of Medicine Doctoral Dissertation Series
Abstract
Breast cancer and type 2 diabetes are major health concerns worldwide. This thesis has focused on novel non-canonical roles of two complement inhibitors, which led to the discovery of new mechanisms and factors at play in these diseases. The sushi domain-containing protein 4 (SUSD4) was previously portrayed as a breast cancer suppressor, but no mechanism was identified. In paper I, using a syngeneic mouse model, we found further support for a tumour-suppressive effect of SUSD4. In triple-negative breast cancer cells, we discovered that SUSD4 interacts with growth factor receptors and promotes autophagy. Our results also indicate a plausible role for SUSD4 in epidermal growth factor receptor trafficking.
CD59, another complement... (More)
Breast cancer and type 2 diabetes are major health concerns worldwide. This thesis has focused on novel non-canonical roles of two complement inhibitors, which led to the discovery of new mechanisms and factors at play in these diseases. The sushi domain-containing protein 4 (SUSD4) was previously portrayed as a breast cancer suppressor, but no mechanism was identified. In paper I, using a syngeneic mouse model, we found further support for a tumour-suppressive effect of SUSD4. In triple-negative breast cancer cells, we discovered that SUSD4 interacts with growth factor receptors and promotes autophagy. Our results also indicate a plausible role for SUSD4 in epidermal growth factor receptor trafficking.
CD59, another complement inhibitor, plays an important non-canonical role in mediating insulin secretion. However, how this surface-anchored protein gains access to the cytoplasm had not been ascertained. In paper II, we identified novel intracellular splice forms of CD59 in both humans and mice that rescue the impaired insulin secretion in CD59-deficient β-cells. In line with this, the isoforms were found to interact with key components of the exocytotic machinery. Our results also indicate a potential link between the CD59 isoforms and the pathogenesis of type 2 diabetes. The role of CD59 in insulin secretion was, in paper III, further explored in a mouse model lacking critical exons of each of the two CD59 genes present in mice. However, the CD59-deficient mice did not exhibit impaired blood glucose homeostasis, and no defect in glucose-stimulated insulin secretion from isolated pancreatic islets was observed. Onwards, we identified a gene product in the CD59-deficient mice composed of the remaining exons of the two CD59 genes spliced together. When expressed in a β-cell line, this gene product could mediate insulin secretion in the absence of CD59, explaining the lack of a phenotype in the mouse model.
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author
supervisor
opponent
  • Group leader, DPhil Olcina del Molino, Monica, Department of Oncology, University of Oxford, UK
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Complement system, SUSD4, CD59, Diabetes mellitus, Type 2 Diabetes, Pancreatic islets, Insulin secretion, Breast cancer, Autophagy, EGFR
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
issue
2025:19
pages
146 pages
publisher
Lund University, Faculty of Medicine
defense location
Medelhavet, Inga Marie Nilssons gata 53, ingång 46, Skånes Universitetssjukhus i Malmö
defense date
2025-02-28 09:00:00
ISSN
1652-8220
ISBN
978-91-8021-672-2
language
English
LU publication?
yes
id
c027ed2f-f465-445d-9ae6-ded1fe541482
date added to LUP
2025-01-28 13:38:04
date last changed
2025-04-04 14:09:34
@phdthesis{c027ed2f-f465-445d-9ae6-ded1fe541482,
  abstract     = {{Breast cancer and type 2 diabetes are major health concerns worldwide. This thesis has focused on novel non-canonical roles of two complement inhibitors, which led to the discovery of new mechanisms and factors at play in these diseases. The sushi domain-containing protein 4 (SUSD4) was previously portrayed as a breast cancer suppressor, but no mechanism was identified. In paper I, using a syngeneic mouse model, we found further support for a tumour-suppressive effect of SUSD4. In triple-negative breast cancer cells, we discovered that SUSD4 interacts with growth factor receptors and promotes autophagy. Our results also indicate a plausible role for SUSD4 in epidermal growth factor receptor trafficking.<br/>CD59, another complement inhibitor, plays an important non-canonical role in mediating insulin secretion. However, how this surface-anchored protein gains access to the cytoplasm had not been ascertained. In paper II, we identified novel intracellular splice forms of CD59 in both humans and mice that rescue the impaired insulin secretion in CD59-deficient β-cells. In line with this, the isoforms were found to interact with key components of the exocytotic machinery. Our results also indicate a potential link between the CD59 isoforms and the pathogenesis of type 2 diabetes. The role of CD59 in insulin secretion was, in paper III, further explored in a mouse model lacking critical exons of each of the two CD59 genes present in mice. However, the CD59-deficient mice did not exhibit impaired blood glucose homeostasis, and no defect in glucose-stimulated insulin secretion from isolated pancreatic islets was observed. Onwards, we identified a gene product in the CD59-deficient mice composed of the remaining exons of the two CD59 genes spliced together. When expressed in a β-cell line, this gene product could mediate insulin secretion in the absence of CD59, explaining the lack of a phenotype in the mouse model.<br/>}},
  author       = {{Ekström, Alexander}},
  isbn         = {{978-91-8021-672-2}},
  issn         = {{1652-8220}},
  keywords     = {{Complement system; SUSD4; CD59; Diabetes mellitus; Type 2 Diabetes; Pancreatic islets; Insulin secretion; Breast cancer; Autophagy; EGFR}},
  language     = {{eng}},
  number       = {{2025:19}},
  publisher    = {{Lund University, Faculty of Medicine}},
  school       = {{Lund University}},
  series       = {{Lund University, Faculty of Medicine Doctoral Dissertation Series}},
  title        = {{Moonlighting complement inhibitors and their link to human diseases}},
  url          = {{https://lup.lub.lu.se/search/files/207221029/PhD_thesis_-_Alexander_Ekstr_m.pdf}},
  year         = {{2025}},
}