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Novel complement regulatory mechanisms in disease

Holmquist, Emelie LU (2015) In Lund University, Faculty of Medicine Doctoral Dissertation Series 2015:100.
Abstract
The complement system is one of the most important defence mechanisms against bacteria and pathogens. It acts within the framework of both innate and adaptive immunity. In addition to direct elimination of pathogens, complement also supports waste removal (dying cells, immune complexes, and misfolded proteins) and guides effector mechanisms of the adaptive immune response. Key events in complement activation are the formation of the C3 and C5 convertase enzyme complexes, the release of chemoattractants, the opsonization with C3b, and cell lysis due to the assembly of the membrane-attack complex (MAC). The proteolytic cascade of the complement system must be tightly regulated, since both excessive and insufficient activation significantly... (More)
The complement system is one of the most important defence mechanisms against bacteria and pathogens. It acts within the framework of both innate and adaptive immunity. In addition to direct elimination of pathogens, complement also supports waste removal (dying cells, immune complexes, and misfolded proteins) and guides effector mechanisms of the adaptive immune response. Key events in complement activation are the formation of the C3 and C5 convertase enzyme complexes, the release of chemoattractants, the opsonization with C3b, and cell lysis due to the assembly of the membrane-attack complex (MAC). The proteolytic cascade of the complement system must be tightly regulated, since both excessive and insufficient activation significantly contributes to the pathology of many diseases. To protect its own cells and tissues, our body expresses several soluble and membrane-bound complement regulators. Here, we study the function of three of these regulators.



Sushi Domain-Containing Protein 4 (SUSD4) is a poorly studied human protein. We show that SUSD4 is a novel complement inhibitor that interferes with the formation of the C3 converts. Additionally, we found that SUSD4 is expressed by breast cancer cells, and that this expression is correlated with a better patient prognosis.



Factor I is a well-known complement inhibitor involved in the degradation of the activation products C4b and C3b. We detected factor I expression in breast cancer, and determined that breast cancer cells are able to produce the proteolytically active form of this protein. Analysis of patient data revealed that factor I expression correlates with poor survival rates.



Cartilage Oligomeric Matrix Protein (COMP) is a large protein involved in the organisation of collagen in the extracellular matrix. We have previously shown that it can both activate and inhibit the complement system. Here, we determined that COMP expression is unregulated in breast cancer tissue where it contributes to a more aggressive form of cancer. COMP expression correlates with poor prognosis and faster recurrence of the disease. Tumors expressing COMP, grown in vivo, were significantly larger and more invasive as compared to control tumors. Interestingly, COMP affected the metabolism and protein processing machinery of the cancer cells, helping them adapt better to a harsh environment.



In summary, this thesis describes novel, disease-related, functions of three complement regulators. (Less)
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author
supervisor
opponent
  • Prof Kirschfink, Michael, University of Heidelberg, Germany
organization
publishing date
type
Thesis
publication status
published
subject
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
volume
2015:100
pages
71 pages
publisher
Department of Medical protein chemistry
defense location
Medelhavet, Wallenberg laboratory, Skånes Universitetssjukhus, Malmö
defense date
2015-11-27 09:00
ISSN
1652-8220
ISBN
978-91-7619-179-8
language
English
LU publication?
yes
id
3301a9fe-9e01-4b61-831f-7df2ba86d07c (old id 8228211)
date added to LUP
2015-11-20 08:53:39
date last changed
2016-09-19 08:44:48
@phdthesis{3301a9fe-9e01-4b61-831f-7df2ba86d07c,
  abstract     = {The complement system is one of the most important defence mechanisms against bacteria and pathogens. It acts within the framework of both innate and adaptive immunity. In addition to direct elimination of pathogens, complement also supports waste removal (dying cells, immune complexes, and misfolded proteins) and guides effector mechanisms of the adaptive immune response. Key events in complement activation are the formation of the C3 and C5 convertase enzyme complexes, the release of chemoattractants, the opsonization with C3b, and cell lysis due to the assembly of the membrane-attack complex (MAC). The proteolytic cascade of the complement system must be tightly regulated, since both excessive and insufficient activation significantly contributes to the pathology of many diseases. To protect its own cells and tissues, our body expresses several soluble and membrane-bound complement regulators. Here, we study the function of three of these regulators.<br/><br>
<br/><br>
Sushi Domain-Containing Protein 4 (SUSD4) is a poorly studied human protein. We show that SUSD4 is a novel complement inhibitor that interferes with the formation of the C3 converts. Additionally, we found that SUSD4 is expressed by breast cancer cells, and that this expression is correlated with a better patient prognosis.<br/><br>
<br/><br>
Factor I is a well-known complement inhibitor involved in the degradation of the activation products C4b and C3b. We detected factor I expression in breast cancer, and determined that breast cancer cells are able to produce the proteolytically active form of this protein. Analysis of patient data revealed that factor I expression correlates with poor survival rates.<br/><br>
<br/><br>
Cartilage Oligomeric Matrix Protein (COMP) is a large protein involved in the organisation of collagen in the extracellular matrix. We have previously shown that it can both activate and inhibit the complement system. Here, we determined that COMP expression is unregulated in breast cancer tissue where it contributes to a more aggressive form of cancer. COMP expression correlates with poor prognosis and faster recurrence of the disease. Tumors expressing COMP, grown in vivo, were significantly larger and more invasive as compared to control tumors. Interestingly, COMP affected the metabolism and protein processing machinery of the cancer cells, helping them adapt better to a harsh environment.<br/><br>
<br/><br>
In summary, this thesis describes novel, disease-related, functions of three complement regulators.},
  author       = {Holmquist, Emelie},
  isbn         = {978-91-7619-179-8},
  issn         = {1652-8220},
  language     = {eng},
  pages        = {71},
  publisher    = {Department of Medical protein chemistry},
  school       = {Lund University},
  series       = {Lund University, Faculty of Medicine Doctoral Dissertation Series},
  title        = {Novel complement regulatory mechanisms in disease},
  volume       = {2015:100},
  year         = {2015},
}