Molecular interactions of PCSK9 with an inhibitory nanobody, CAP1 and HLA-C: Functional regulation of LDLR levels

Gaillard, Carole Fruchart; Ouadda, Ali Ben Djoudi; Ciccone, Lidia; Girard, Emmanuelle; Mikaeeli, Sepideh; Evagelidis, Alexandra; Dévéhat, Maïlys Le; Susan‐Resiga, Delia; Lajeunesse, Evelyne; Nozach, Hervé; Ramos, Oscar Henrique Pereira; Thureau, Aurélien; Legrand, Pierre; Prat, Annik; Dive, Vincent; Seidah, Nabil G.

doi:10.1016/j.molmet.2022.101662

Cited by 6 publications

(62 citation statements)

References 70 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“… 34 Our understanding of the PCSK9-MHC-I interaction was further supported by a recent study suggesting a potentially crucial role for HLA-C or a similar candidate from the MHC-I family in directing the PCSK9-LDLR complex towards lysosomes for degradation by interacting with PCSK9’s M2 domain. 86 Therefore, our investigation revealed a potential non-canonical role of PCSK9 in regulating MHC-I levels to modulate TIME, indicating that PCSK9 may be a robust target to enhance cancer immunotherapy (Fig. 3b ).…”

Section: The Role Of Pcsk9 In Various Disordersmentioning

confidence: 73%

“…Jang et al found that cytosolic CAP1, which can bind resistin, could bind the M1 and M3 modules of PCSK9’s CHRD, promoting the lysosomal degradation of the PCSK9-LDLR complex. 85 , 86 Another group argued that HLA-C or a similar major histocompatibility complex class I (MHC-I) family member could guide the LDLR-PCSK9-CAP1 complex to degradation 86 (Fig. 1b ).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Targeting proprotein convertase subtilisin/kexin type 9 (PCSK9): from bench to bedside

Bao,

Liang,

Chang

et al. 2024

Sig Transduct Target Ther

View full text Add to dashboard Cite

Proprotein convertase subtilisin/kexin type 9 (PCSK9) has evolved as a pivotal enzyme in lipid metabolism and a revolutionary therapeutic target for hypercholesterolemia and its related cardiovascular diseases (CVD). This comprehensive review delineates the intricate roles and wide-ranging implications of PCSK9, extending beyond CVD to emphasize its significance in diverse physiological and pathological states, including liver diseases, infectious diseases, autoimmune disorders, and notably, cancer. Our exploration offers insights into the interaction between PCSK9 and low-density lipoprotein receptors (LDLRs), elucidating its substantial impact on cholesterol homeostasis and cardiovascular health. It also details the evolution of PCSK9-targeted therapies, translating foundational bench discoveries into bedside applications for optimized patient care. The advent and clinical approval of innovative PCSK9 inhibitory therapies (PCSK9-iTs), including three monoclonal antibodies (Evolocumab, Alirocumab, and Tafolecimab) and one small interfering RNA (siRNA, Inclisiran), have marked a significant breakthrough in cardiovascular medicine. These therapies have demonstrated unparalleled efficacy in mitigating hypercholesterolemia, reducing cardiovascular risks, and have showcased profound value in clinical applications, offering novel therapeutic avenues and a promising future in personalized medicine for cardiovascular disorders. Furthermore, emerging research, inclusive of our findings, unveils PCSK9’s potential role as a pivotal indicator for cancer prognosis and its prospective application as a transformative target for cancer treatment. This review also highlights PCSK9’s aberrant expression in various cancer forms, its association with cancer prognosis, and its crucial roles in carcinogenesis and cancer immunity. In conclusion, this synthesized review integrates existing knowledge and novel insights on PCSK9, providing a holistic perspective on its transformative impact in reshaping therapeutic paradigms across various disorders. It emphasizes the clinical value and effect of PCSK9-iT, underscoring its potential in advancing the landscape of biomedical research and its capabilities in heralding new eras in personalized medicine.

show abstract

Section: The Role Of Pcsk9 In Various Disordersmentioning

confidence: 73%

Section: Introductionmentioning

confidence: 99%

Targeting proprotein convertase subtilisin/kexin type 9 (PCSK9): from bench to bedside

Bao,

Liang,

Chang

et al. 2024

Sig Transduct Target Ther

View full text Add to dashboard Cite

show abstract

“…The M2 module of PCSK9 was recently shown to bind an exposed R-X-E motif in some MHC-I receptors, leading to their enhanced degradation in lysosomes, independently from the LDLR [ 33 , 63 ]. We have also recently reported that MHC-I receptors such as HLA-C enhance the PCSK9-induced degradation of the LDLR by efficiently targeting the LDLR-PCSK9-HLA-C complex to lysosomes [ 64 , 65 ].…”

Section: Resultsmentioning

confidence: 99%

“…This may in part rationalize why ACE2 seems to inhibit PCSK9′s ability to enhance the degradation of the LDLR ( Figure 7 D). Recently, we reported a detailed analysis of the PCSK9-LDLR complex trafficking to endosomes/lysosomes for degradation [ 64 , 65 ]. The study implicated two other proteins for the effective targeting of the complex for lysosomal degradation: the cyclase associated protein 1 (CAP1) binding the prodomain and the M1/M3 domains of PCSK9 and HLA-C (an MHC-I family member) binding the M2 domain of PCSK9.…”

Section: Discussionmentioning

confidence: 99%

SKI-1/S1P Facilitates SARS-CoV-2 Spike Induced Cell-to-Cell Fusion via Activation of SREBP-2 and Metalloproteases, Whereas PCSK9 Enhances the Degradation of ACE2

Essalmani

Andréo

Evagelidis

et al. 2023

Viruses

View full text Add to dashboard Cite

Proprotein convertases activate various envelope glycoproteins and participate in cellular entry of many viruses. We recently showed that the convertase furin is critical for the infectivity of SARS-CoV-2, which requires cleavage of its spike protein (S) at two sites: S1/S2 and S2′. This study investigates the implication of the two cholesterol-regulating convertases SKI-1 and PCSK9 in SARS-CoV-2 entry. The assays used were cell-to-cell fusion in HeLa cells and pseudoparticle entry into Calu-3 cells. SKI-1 increased cell-to-cell fusion by enhancing the activation of SREBP-2, whereas PCSK9 reduced cell-to-cell fusion by promoting the cellular degradation of ACE2. SKI-1 activity led to enhanced S2′ formation, which was attributed to increased metalloprotease activity as a response to enhanced cholesterol levels via activated SREBP-2. However, high metalloprotease activity resulted in the shedding of S2′ into a new C-terminal fragment (S2”), leading to reduced cell-to-cell fusion. Indeed, S-mutants that increase S2′’ formation abolished S2′ and cell-to-cell fusion, as well as pseudoparticle entry, indicating that the formation of S2′’ prevents SARS-CoV-2 cell-to-cell fusion and entry. We next demonstrated that PCSK9 enhanced the cellular degradation of ACE2, thereby reducing cell-to-cell fusion. However, different from the LDLR, a canonical target of PCSK9, the C-terminal CHRD domain of PCSK9 is dispensable for the PCSK9-induced degradation of ACE2. Molecular modeling suggested the binding of ACE2 to the Pro/Catalytic domains of mature PCSK9. Thus, both cholesterol-regulating convertases SKI-1 and PCSK9 can modulate SARS-CoV-2 entry via two independent mechanisms.

show abstract

“…The mechanism by which the extracellular PCSK9-LDLR complex is sorted to lysosomal compartments is not fully understood. However, the CHRD domain appears to play a critical role in this process by facilitating the interaction between PCSK9 and an unidentified partner protein referred to as "protein X" [20,23]. This interaction is essential for directing the PCSK9-LDLR heterodimer to endosomes/lysosomes for degradation.…”

Section: Introductionmentioning

confidence: 99%

Insights Into PCSK9-LDLR Regulation and Trafficking Via the Differential Functions of MHC-I Proteins HFE and HLA-C

Mikaeeli,

Ben Djoudi Ouadda,

Evagelidis

et al. 2024

Preprint

View full text Add to dashboard Cite

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.

show abstract

Molecular interactions of PCSK9 with an inhibitory nanobody, CAP1 and HLA-C: Functional regulation of LDLR levels

Cited by 6 publications

References 70 publications

Targeting proprotein convertase subtilisin/kexin type 9 (PCSK9): from bench to bedside

Targeting proprotein convertase subtilisin/kexin type 9 (PCSK9): from bench to bedside

SKI-1/S1P Facilitates SARS-CoV-2 Spike Induced Cell-to-Cell Fusion via Activation of SREBP-2 and Metalloproteases, Whereas PCSK9 Enhances the Degradation of ACE2

Insights Into PCSK9-LDLR Regulation and Trafficking Via the Differential Functions of MHC-I Proteins HFE and HLA-C

Contact Info

Product

Resources

About