👤 Julius L Katzmann

On the basis of life-style changes and statins, current guidelines recommend early combination therapy to reduce LDL cholesterol (LDL-C). Available and future novel non-statin lipid-lowering therapies may have specific advantages in patients with (1) statin intolerance, (2) elevated triglyceride-rich lipoproteins, (3) elevated lipoprotein(a), and (4) rare genetic dyslipidemias. Currently available treatment options to lower LDL-C with proven cardiovascular benefit include statins, ezetimibe, bempedoic acid, and PCSK9 antibodies. The 2025 update of the ESC/EAS dyslipidemia guidelines incorporates recommendations on early combination treatment and management of rare dyslipidemias, which are detailed in this review. Novel LDL-C-lowering strategies, targeting PCSK9 and CETP, may further improve dyslipidemia management. Drugs in development with profound effects on lipoprotein(a) or triglyceride concentration may allow for specific modification of residual cardiovascular risk. Innovative DNA-targeting therapies are moving towards clinical testing in larger studies. Various treatment options for patients with dyslipidemia and distinct characteristics have become available. Future developments may allow for even more tailored treatment, depending on dyslipidemia phenotype. Show less

Ubiquitin modification of endosomal membrane proteins is a signal for active inclusion into the Multivesicular Body (MVB) pathway, resulting in lysosomal degradation. However, the endosome represents a dynamic site of protein sorting with a majority of proteins destined for recycling, rather than MVB targeting. Substrate recognition by ubiquitin ligases is therefore highly regulated. We have investigated substrate recognition by the Nedd4 ortholog Rsp5 as a model for understanding ligase-substrate interactions. Rsp5 interacts directly with its substrate Cps1 via a novel interaction mode. Perturbation of this mode of interaction revealed a compensatory role for the Rsp5 adaptor Bsd2. These results highlight the ability of Rsp5 to interact with substrates via multiple modalities, suggesting additional mechanisms of regulating this interaction and relevant outcomes. Show less

Ubiquitin (Ub) sorting receptors facilitate the targeting of ubiquitinated membrane proteins into multivesicular bodies (MVBs). Ub-binding domains (UBDs) have been described in several endosomal sorting complexes required for transport (ESCRT). Using available structural information, we have investigated the role of the multiple UBDs within ESCRTs during MVB cargo selection. We found a novel UBD within ESCRT-I and show that it contributes to MVB sorting in concert with the known UBDs within the ESCRT complexes. These experiments reveal an unexpected level of coordination among the ESCRT UBDs, suggesting that they collectively recognize a diverse set of cargo rather than act sequentially at discrete steps. Show less

The multivesicular body (MVB) sorting pathway provides a mechanism for delivering transmembrane proteins into the lumen of the lysosome/vacuole. Recent studies demonstrated that ubiquitin modification acts in cis as a signal for the sorting of cargoes into this pathway. Here, we present results from a genetic selection designed to identify mutants that missort MVB cargoes. This selection identified a point mutation in ubiquitin ligase Rsp5 (Rsp5-326). At the permissive temperature, this mutant is specifically defective for ubiquitination and sorting of the ubiquitin-dependent MVB cargo precursor carboxypeptidase S (pCPS), but not ligand-induced ubiquitination of Ste2. A previous study implicated Tul1 as the ubiquitin ligase responsible for MVB sorting of pCPS. However, we detected no defect in either the sorting or ubiquitination of pCPS in tul1 mutants. We had previously shown that Fab1 phosphatidylinositol 3-phosphate 5-kinase is also required for MVB sorting of pCPS, but not Ste2. However, our analyses reveal that fab1 mutants do not exhibit a defect in ubiquitination of pCPS. Thus, both Rsp5 and Fab1 play distinct and essential roles in the targeting of biosynthetic MVB cargoes. However, whereas Rsp5 seems to be responsible for cargo ubiquitination, the precise role for Fab1 remains to be elucidated. Show less