Regulation of PCSK9 Levels by the Ubiquitin‐Binding Domain of Histone Deacetylase 6

Abstract

Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) regulates plasma lipid homeostasis by altering the abundance of low‐density lipoprotein(LDL)‐receptors in the liver. Therefore, this critical role in lipid homeostasis makes PCSK9 an attractive target for the therapeutic management of familial hypercholesterolemia as well as other refractory dyslipidemias. Recently, monoclonal antibodies that bind circulating PCSK9 were approved for therapeutic use to reduce LDL‐C levels to control hypercholesterolemia. However, other strategies to inhibit PCSK9 have not as yet been explored. We have recently demonstrated that HDAC6, a class IIB deacetylase, is a potent regulator of PCSK9 levels. Our data show that co‐expression of PCSK9 with full length HDAC6 in 293A cells results in marked upregulation of PCSK9, while gene silencing of endogenous HDAC6 leads to reduction in PCSK9. Interestingly, this effect was found to be independent of the deacetylase activity of HDAC6 and dependent upon the unique ubiquitin‐binding (BUZ) domain located at the C‐terminal tail of HDAC6. Small molecule inhibition of HDAC6 activity by Tubacin in vivo in hypercholesterolemic ApoE knockout mice had no effect on liver PCSK9 and LDL receptor levels. Further, co‐expression of the catalytic deficient mutant of HDAC6 (H216/611A) with PCSK9 did not modulate the high PCSK9 levels. The effect of HDAC6 on PCSK9 abundance was abolished when PCSK9 was co‐expressed with a BUZ domain deletion mutant of HDAC6. Our co‐immunoprecipitation data further suggest that HDAC6 binds to the polyubiquitin chain of PCSK9, recruits the deubiquitinating enzyme USP7 and protects PCSK9 from degradation. These signaling events lead to augmented PCSK9, followed by reduction of LDLr in liver, and eventually to hyperlipidemia.Our data indicate that the HDAC6 BUZ domain regulates PCSK9 levels via post‐translational modification by deubiquitinase USP7, and this may represent a novel target for hyperlipidemia.Support or Funding InformationAmerican Heart Association Scientist Development Grant (16SDG27340010) Gilead Sciences Pulmonary Arterial Hypertension Research Scholar AwardThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.