The CCC Complex COMManDs Control of LDL Cholesterol Levels.

Abstract

The LDLR (low-density lipoprotein [LDL] receptor) plays a key role in the regulation of plasma LDL cholesterol levels, and loss of function mutations in the LDLR result in familial hypercholesterolemia.1 After binding of LDL at the cell surface, LDLR is endocytosed via clathrin-coated pits.2 On release of its cargo, it is then recycled back to the plasma membrane. Alternatively, LDLR can be targeted to the lysosome for degradation via either PCSK9 (proprotein convertase subtilisin/kexin type 9)3 or IDOL (inducible degrader of the LDLR),4 in turn reducing LDL uptake. In this issue of Circulation Research , Fedoseienko et al5 demonstrate that LDLR recycling to the cell surface is reliant on an intact CCC (COMMD [copper metabolism MURR1 domain]–CCDC [coiled-coil domain-containing] 22–CCDC93) complex, as well as expression of all COMMD family members. When the integrity of this pathway is compromised, hypercholesterolemia and atherosclerosis ensue. Article, see p 1648 COMMD 1 is 1 of 10 COMMD family members and was initially identified for its role in regulating copper homeostasis.6,7 van de Sluis et al provided a link between COMMD1 and copper transport, demonstrating that COMMD1, together with CCDC22 and CCDC93, as well as the WASH (Wiskott–Aldrich syndrome protein and SCAR homologue) complex, regulates endosomal trafficking of the copper transporter, ATP7A (ATPase copper transporting alpha).8 Subsequent studies by this team demonstrated that this same mechanism is involved in endosomal trafficking of the LDLR9 (Figure). They reported that deficiency of COMMD1 resulted in impaired LDLR recycling and reduced LDL uptake. Moreover, depletion or mutations in components of the CCC complex, including Commd1 or Commd9 or Ccdc22 , resulted in elevated circulating cholesterol levels in dogs, mice, and humans, respectively. …