HMGCR is subject to Insig-dependent, sterol-accelerated ERAD. gp78 was reported to target HMGCR and Insig-1 for ubiquitination and degradation. Here gp78-mediated Insig-1 degradation is confirmed, but no role for gp78 is found in regulated ERAD of HMGCR. The identity of the HMGCR E3(s) and mechanistic details of HMGCR degradation await further study.

Generalized lymphatic anomaly (GLA or lymphangiomatosis) is a rare disease characterized by a diffuse proliferation of lymphatic vessels in skin and internal organs. It often leads to progressive respiratory failure and death, but its etiology is unknown. Here, we isolated lymphangiomatosis endothelial cells from GLA tissue. These cells were characterized by high proliferation and survival rates, but displayed impaired capacities for migration and tube formation. We employed whole exome sequencing to search for disease-causing genes and identified a somatic mutation in NRAS. We used mouse and zebrafish model systems to initially evaluate the role of this mutation in the development of the lymphatic system, and we studied the effect of drugs blocking the downstream effectors, mTOR and ERK, on this disease.

The stability of the endoplasmic reticulum (ER) glycoprotein 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR), the key enzyme in cholesterol biosynthesis, is negatively regulated by sterols. HMGR is anchored in the ER via its N-terminal region, which spans the membrane eight times and contains a sterolsensing domain. We have previously established that degradation of mammalian HMGR is mediated by the ubiquitin-proteasome system (Ravid, T., Doolman, R., Avner, R., Harats, D., and Roitelman, J. (2000) 89 and Lys 248 attenuate ubiquitination at the latter residues. The ATP-dependent ubiquitination of HMGR in isolated microsomes requires E1 as the sole cytosolic protein, indicating that ER-bound E2 and E3 enzymes catalyze this modification. Polyubiquitination of HMGR is correlated with its extraction from the ER membrane, a process likely to be assisted by cytosolic p97/VCP/Cdc48p-Ufd1-Npl4 complex, as only ubiquitinated HMGR pulls down p97.The enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) 1 catalyzes the rate-limiting production of mevalonate, the committed precursor for the biosynthesis of sterols and a myriad of essential nonsterol isoprenoids. The intracellular levels of HMGR are regulated by the cellular needs for sterol and nonsterol metabolites. This regulation involves changes in the transcription of the HMGR gene and, at the post-translational level, alteration of enzyme stability (1-3). Thus, when demands for sterols are high, HMGR gene is transcribed at a high rate, and the resulting HMGR protein is relatively stable. When the requirements for mevalonate-derived metabolites have been satisfied, transcription ceases, and the enzyme is rapidly degraded (1-3).