Skip to main content

LUP Student Papers

LUND UNIVERSITY LIBRARIES

Functions of CD59 isoforms IRIS-1 and IRIS-2 in pancreatic β-cells

Kasbauer, Vanessa (2025) MOBN02 20242
Degree Projects in Molecular Biology
Abstract
Type 2 diabetes is characterized by pancreatic β-cell dysfunction and insulin resistance. There are various studies about the contributing molecular mechanisms, and our recent findings show that the complement inhibitor Cd59 might play a non-canonical role in insulin secretion. Specifically, knock-out of Cd59 greatly inhibits glucose-stimulated insulin secretion. This, however, can be rescued by two novel intracellular splicing isoforms of CD59 called Isoforms Rescuing Insulin Secretion 1 and 2, short IRIS-1 and IRIS-2. To understand the mechanisms of IRIS-1/IRIS-2 in pancreatic β-cells, we first identified their binding partners. Our preliminary data suggests that Noc2, an effector of the essential membrane trafficking process, is a... (More)
Type 2 diabetes is characterized by pancreatic β-cell dysfunction and insulin resistance. There are various studies about the contributing molecular mechanisms, and our recent findings show that the complement inhibitor Cd59 might play a non-canonical role in insulin secretion. Specifically, knock-out of Cd59 greatly inhibits glucose-stimulated insulin secretion. This, however, can be rescued by two novel intracellular splicing isoforms of CD59 called Isoforms Rescuing Insulin Secretion 1 and 2, short IRIS-1 and IRIS-2. To understand the mechanisms of IRIS-1/IRIS-2 in pancreatic β-cells, we first identified their binding partners. Our preliminary data suggests that Noc2, an effector of the essential membrane trafficking process, is a potential candidate. We therefore hypothesized that Cd59 isoforms might facilitate insulin secretion via Noc2. Additionally, we tested whether IRIS-1/IRIS-2 can prevent glycogen accumulation in β-cells, an impaired metabolic feature in type 2 diabetes. Using the rat-derived ß-cell model INS-1 832/13, we observed that Noc2 protein but not mRNA level, was significantly increased in Cd59 knock-out cells, but restored when IRIS-1 or IRIS-2 was overexpressed. In situ proximity ligation assay showed a significant colocalization of Cd59/IRIS-1/IRIS-2 with Noc2, which supports a possible interaction. Colocalization, however, seemed unaffected by low/high-glucose conditions. Moreover, direct protein-protein interaction as well as metabolic effects of the isoforms on glycogen levels still need more investigation. In conclusion, our data indicates a regulatory relationship on the protein level and delivers preliminary evidence for physical interaction between Noc2 and IRIS-1/IRIS-2. Optimization of experiments and validation in other model systems is needed to confirm our hypothesis and unravel the importance of Cd59 isoforms in pancreatic β-cells. (Less)
Popular Abstract
When an Inhibitor Helps: Cd59 and Insulin Secretion

One cause of type 2 diabetes is the failure of pancreatic ß-cells to release enough insulin, the essential hormone for regulating blood sugar. Researchers are still trying to understand why ß-cells stop functioning properly. Surprisingly, the cell surface protein Cd59, which is mostly known for protecting cells against the body’s own immune attacks, has recently been linked to insulin secretion. When Cd59 is removed from ß-cells, insulin release is impaired. However, two newly discovered intracellular versions of CD59, called IRIS-1 and IRIS-2, can restore insulin secretion when present in the cell. This thesis aimed to understand how IRIS-1/IRIS-2 could help with insulin secretion.

... (More)
When an Inhibitor Helps: Cd59 and Insulin Secretion

One cause of type 2 diabetes is the failure of pancreatic ß-cells to release enough insulin, the essential hormone for regulating blood sugar. Researchers are still trying to understand why ß-cells stop functioning properly. Surprisingly, the cell surface protein Cd59, which is mostly known for protecting cells against the body’s own immune attacks, has recently been linked to insulin secretion. When Cd59 is removed from ß-cells, insulin release is impaired. However, two newly discovered intracellular versions of CD59, called IRIS-1 and IRIS-2, can restore insulin secretion when present in the cell. This thesis aimed to understand how IRIS-1/IRIS-2 could help with insulin secretion.

All cellular processes rely on protein interactions. Therefore, the identification of IRIS-1 and IRIS-2 binding partners is essential to understand their function. We focused on one candidate binding partner called Noc2, which plays a role in the transport and release of insulin. We hypothesized that IRIS-1/IRIS-2 might work together with Noc2 in the process of insulin secretion. To explore this, we studied whether Noc2 levels change in the presence or absence of Cd59/IRIS-1/IRIS-2, and whether they can physically interact. We also tested if IRIS-1/IRIS-2 influence ß-cell metabolism by preventing glycogen buildup, a harmful process observed in type 2 diabetes.

Our results show that Noc2 protein levels rise when Cd59 is absent from β-cells but remain unchanged when IRIS-1 or IRIS-2 are present, suggesting that these new versions help to maintain normal Noc2 levels. This regulation appears to occur at the protein, not gene, level.

To validate that two proteins can interact, they not only need to be able to physically bind to each other but also need to lie close together in the cell, so that interaction can take place. We found increased colocalization of Noc2 with IRIS-1 and IRIS-2 compared to cells that lack Cd59. This supports the idea of a specific interaction (Figure 1). However, we are still working on a proper protocol to prove a direct binding between Noc2 and IRIS-1/IRIS-2. For investigating the glycogen accumulation, our detection method also requires further refinement.

In conclusion, our research suggests a potential regulatory relationship between IRIS-1/IRIS-2 and Noc2 on the protein level, with preliminary evidence supporting their interaction. While some experiments need refinement, our data adds to the understanding of how intracellular versions of Cd59 might influence insulin secretion, offering new insights into β-cell function and type 2 diabetes.


Master’s Degree Project in Molecular Biology 45 credits 2024/25
Department of Biology, Lund University

Advisors: Prof. Anna Blom and Dr. Thu-Ha Tran
Department of Translational Medicine, Lund University (Less)
Please use this url to cite or link to this publication:
author
Kasbauer, Vanessa
supervisor
organization
course
MOBN02 20242
year
type
H2 - Master's Degree (Two Years)
subject
language
English
id
9214675
date added to LUP
2025-10-30 09:53:41
date last changed
2025-10-30 09:53:41
@misc{9214675,
  abstract     = {{Type 2 diabetes is characterized by pancreatic β-cell dysfunction and insulin resistance. There are various studies about the contributing molecular mechanisms, and our recent findings show that the complement inhibitor Cd59 might play a non-canonical role in insulin secretion. Specifically, knock-out of Cd59 greatly inhibits glucose-stimulated insulin secretion. This, however, can be rescued by two novel intracellular splicing isoforms of CD59 called Isoforms Rescuing Insulin Secretion 1 and 2, short IRIS-1 and IRIS-2. To understand the mechanisms of IRIS-1/IRIS-2 in pancreatic β-cells, we first identified their binding partners. Our preliminary data suggests that Noc2, an effector of the essential membrane trafficking process, is a potential candidate. We therefore hypothesized that Cd59 isoforms might facilitate insulin secretion via Noc2. Additionally, we tested whether IRIS-1/IRIS-2 can prevent glycogen accumulation in β-cells, an impaired metabolic feature in type 2 diabetes. Using the rat-derived ß-cell model INS-1 832/13, we observed that Noc2 protein but not mRNA level, was significantly increased in Cd59 knock-out cells, but restored when IRIS-1 or IRIS-2 was overexpressed. In situ proximity ligation assay showed a significant colocalization of Cd59/IRIS-1/IRIS-2 with Noc2, which supports a possible interaction. Colocalization, however, seemed unaffected by low/high-glucose conditions. Moreover, direct protein-protein interaction as well as metabolic effects of the isoforms on glycogen levels still need more investigation. In conclusion, our data indicates a regulatory relationship on the protein level and delivers preliminary evidence for physical interaction between Noc2 and IRIS-1/IRIS-2. Optimization of experiments and validation in other model systems is needed to confirm our hypothesis and unravel the importance of Cd59 isoforms in pancreatic β-cells.}},
  author       = {{Kasbauer, Vanessa}},
  language     = {{eng}},
  note         = {{Student Paper}},
  title        = {{Functions of CD59 isoforms IRIS-1 and IRIS-2 in pancreatic β-cells}},
  year         = {{2025}},
}