Investigating the novel interaction between hERG and the Fc region of IgG and its consequences

The human ether-a-go-go related gene (hERG; KCNH2) encodes the pore-forming subunit of the Kv11.1 channel which conducts the rapidly activating delayed rectifier potassium current (IKr). Impairment of hERG function is responsible for the form of acquired long QT syndrome (LQTS) observed in certain autoimmune patients. Previously, our lab identified the autoantibody anti-Ro52 to interact with hERG and reduce its expression on the cell surface, however the exact mechanism for this is not well characterized. Here, Western blot analysis and whole-cell patch clamping were used to analyze hERG expression and function in hERG-expressing human embryonic kidney (HEK) cells. In addition to anti-Ro52, several IgG antibodies were found to interact with hERG and induce chronic channel internalization, reducing hERG current (IhERG) by 23-56%, with the Fc region in particular identified to solely convey these effects through binding to the S5-pore linker. Moreover, we demonstrate that a previously overlooked immunoreceptor tyrosine-based inhibitory motif (ITIM) within the C-terminus of hERG is necessary for this internalization, with its substitution (Y827A) completely preventing this effect. Inhibition of both Src and Src homology region 2 domain-containing phosphatases (SHP) further mitigate IgG’s effects highlighting their involvement in this mechanism. These findings provide molecular insights into the incidence of LQTS observed in not only autoimmune patients but also patients receiving certain monoclonal antibody therapies. Interestingly, IgG was identified to promote cell death in specifically hERG-expressing cells. Moreover, inhibition of the pro-apoptotic large tumour suppressor kinases (LATS) was identified to alleviate IgG’s effects, suggesting a link between its interaction with hERG and cell death. This is the first evidence of a mechanistic role for this hERG-ITIM and provides insights into not only the role of hERG in antibody-induced LQTS but also its potential role in mediating cell death.

Department dc:contributor.department

Biomedical and Molecular Sciences

Year dc:date.issued

2024

Author dc:creator

• Cornwell, James Duncan

Advisor dc:contributor.supervisor

• Zhang, Shetuan

• hERG
• electrophysiology
• molecular biology
• LQTS
• ITIM
• IgG

Language dc:language.iso

eng

Handle dc:identifier.uri

https://hdl.handle.net/1974/33326

OAI identifier oai:identifier

oai:queensu.scholaris.ca:1974/33326