Version 1
: Received: 15 March 2024 / Approved: 18 March 2024 / Online: 18 March 2024 (16:09:58 CET)
How to cite:
Mikaeeli, S.; Ben Djoudi Ouadda, A.; Evagelidis, A.; Essalmani, R.; Pereira Ramos, O.H.; Fruchart-Gaillard, C.; Seidah, N.G.G. Insights Into PCSK9-LDLR Regulation and Trafficking Via the Differential Functions of MHC-I Proteins HFE and HLA-C. Preprints2024, 2024031047. https://doi.org/10.20944/preprints202403.1047.v1
Mikaeeli, S.; Ben Djoudi Ouadda, A.; Evagelidis, A.; Essalmani, R.; Pereira Ramos, O.H.; Fruchart-Gaillard, C.; Seidah, N.G.G. Insights Into PCSK9-LDLR Regulation and Trafficking Via the Differential Functions of MHC-I Proteins HFE and HLA-C. Preprints 2024, 2024031047. https://doi.org/10.20944/preprints202403.1047.v1
Mikaeeli, S.; Ben Djoudi Ouadda, A.; Evagelidis, A.; Essalmani, R.; Pereira Ramos, O.H.; Fruchart-Gaillard, C.; Seidah, N.G.G. Insights Into PCSK9-LDLR Regulation and Trafficking Via the Differential Functions of MHC-I Proteins HFE and HLA-C. Preprints2024, 2024031047. https://doi.org/10.20944/preprints202403.1047.v1
APA Style
Mikaeeli, S., Ben Djoudi Ouadda, A., Evagelidis, A., Essalmani, R., Pereira Ramos, O.H., Fruchart-Gaillard, C., & Seidah, N.G.G. (2024). Insights Into PCSK9-LDLR Regulation and Trafficking Via the Differential Functions of MHC-I Proteins HFE and HLA-C. Preprints. https://doi.org/10.20944/preprints202403.1047.v1
Chicago/Turabian Style
Mikaeeli, S., Carole Fruchart-Gaillard and Nabil G. G Seidah. 2024 "Insights Into PCSK9-LDLR Regulation and Trafficking Via the Differential Functions of MHC-I Proteins HFE and HLA-C" Preprints. https://doi.org/10.20944/preprints202403.1047.v1
Abstract
PCSK9 is implicated in familial hypercholesterolemia via targeting the cell surface PCSK9-LDLR complex toward lysosomal degradation. The M2 repeat in the PCSK9's C-terminal domain is essential for its extracellular function, potentially through its interaction with an unidentified “protein X”. The M2 repeat was recently shown to bind an R-x-E motif in MHC-class-I proteins (implicated in the immune system), like HLA-C, and causing their lysosomal degradation. These findings suggested a new role of PCSK9 in the immune system and that HLA-like proteins could be “protein X” candidates. However, the participation of each member of the MHC-I protein family in this process and their regulation of PCSK9's function have yet to be determined. Herein, we compared the implication of MHC-I-like proteins such as HFE (involved in iron homeostasis) and HLA-C on the extracellular function of PCSK9. Our data revealed that the M2 domain regulates the intracellular sorting of the PCSK9-LDLR complex to lysosomes, and that HFE is a new target of PCSK9 that inhibits its activity on the LDLR, whereas HLA-C enhances its function. This work suggests the potential modulation of the PCSK9 functions through interactions of HFE and HLA-C.
Keywords
PCSK9; LDLR; HFE; HLA-C; MHC-I; lipid metabolism
Subject
Biology and Life Sciences, Biochemistry and Molecular Biology
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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