Regulation of PCSK9 Expression and Function: Mechanisms and Therapeutic Implications

Abstract

Proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes degradation of low-density lipoprotein receptor (LDLR) and plays a central role in regulating plasma levels of LDL cholesterol levels, lipoprotein(a) and triglyceride-rich lipoproteins, increasing the risk of cardiovascular disease. Additionally, PCSK9 promotes degradation of major histocompatibility protein class I and reduces intratumoral infiltration of cytotoxic T cells. Inhibition of PCSK9 increases expression of LDLR, thereby reducing plasma levels of lipoproteins and the risk of cardiovascular disease. PCSK9 inhibition also increases cell surface levels of major histocompatibility protein class I in cancer cells and suppresses tumor growth. Therefore, PCSK9 plays a vital role in the pathogenesis of cardiovascular disease and cancer, the top two causes of morbidity and mortality worldwide. Monoclonal anti-PCSK9 antibody-based therapy is currently the only available treatment that can effectively reduce plasma LDL-C levels and suppress tumor growth. However, high expenses limit their widespread use. PCSK9 promotes lysosomal degradation of its substrates, but the detailed molecular mechanism by which PCSK9 promotes degradation of its substrates is not completely understood, impeding the development of more cost-effective alternative strategies to inhibit PCSK9. Here, we review our current understanding of PCSK9 and focus on the regulation of its expression and functions.

Keywords: LDL receptor; PCSK9; atherosclerosis; cancer immunotherapy; cardiovascular disease; lipid metabolism; major histocompatibility protein class I.

Figure 1

PCSK9, LDLR, and MHCI. PCSK9 is auto-cleaved in the ER. Mature PCSK9 is transported to the Golgi and then secreted. PCSK9 binds to LDLR and MHCI on the cell surface. After, the complex is delivered to endosomes via endocytosis and then transported to the lysosome for degradation. LDLR binds to its ligands such as LDL, VLDL, and Lp(a) and then the receptor/ligand complex enters cells via receptor-mediated endocytosis and is delivered to the endosome. In the acidic endosomal environment, the ligand, such as LDL, is released from LDLR and transported to the lysosome for degradation. LDLR is recycled to plasma membrane. PCSK9-promoted degradation of LDLR increases plasma levels of LDL and Lp(a). Pro, prodomain; CAT, catalytic domain; CTD, C-terminal domain.

Figure 2

Regulation of PCSK9 expression. Transcriptional factors, such as SREBP2, HNF-1α, SP-1and E2F2, upregulate PCSK9 transcription. FGF21 and resistin inhibit and increase SREBP2-mediated transcription of PCSK9, respectively. Barberine reduces PCSK9 expression via suppressing the activity of SREBP2 and HNF-1α on PCSK9 transcription. 9K suppresses PCSK9 expression through SP1 and HNF-1α, while Curcumin, 7030B-C5 inhibits HNF-1α-induced transcription of PCSK9. Alcohol use causes hypomethylation of PCSK9 promoter and then reduces PCSK9 expression. Insulin activates mTROC1 and then PKCδ to suppress PCSK9 transcription via HNF-1α. miR-483-5p, miR-1228-3p, miR-143-5p, miR-564, and miR-4721 bind to the 3'UTR of PCSK9 mRNA, reducing PCSK9 expression, while miR27a somehow increases PCSK9 expression. R-IMPP inhibits 80S ribosome and reduces PCSK9 expression. After autocleavage in the ER, PCSK9 is transported to the Golgi via classical COPII vesicles. There, PCSK9 undergoes posttranslational modifications, such as phosphorylation, glycosylation, and sulfation. Mature PCSK9 is then secreted into the extra cellular environment.