Reticulophagy regulator 1 (RETREG1)/Family with sequence similarity 134 member B (FAM134B) is a selective endoplasmic reticulum (ER)-phagy receptor that mediates starvation-induced macro-ER-phagy, but Show more
Reticulophagy regulator 1 (RETREG1)/Family with sequence similarity 134 member B (FAM134B) is a selective endoplasmic reticulum (ER)-phagy receptor that mediates starvation-induced macro-ER-phagy, but whether it participates in other pathways mediating ER turnover has remained unclear. Here, we unveil a previously unrecognized role for RETREG1 in micro-ER-phagy and show how the murine leukemia virus (MLV) accessory protein glycosylated group-specific antigen (glycoGag) exploits this pathway to antagonize the host restriction factor SERINC5 (serine incorporator 5). GlycoGag binds SERINC5 in the endoplasmic reticulum (ER) and selectively recruits RETREG1 to eliminate SERINC5 through an autophagosome-independent process that bypasses ATG3 (autophagy-related), ATG5, ATG7, BECN1 (Beclin-1), LC3 (microtubule-associated protein 1 light chain 3) lipidation, and PIK3C3 (phosphatidylinositol 3-kinase catalytic subunit type 3)/hVPS34 (vacuolar protein sorting 34). RETREG1 knockout abolishes degradation of ER-retained SERINC5, whereas endolysosomal turnover of surface SERINC5 remains partially intact, demonstrating that glycoGag utilizes dual ER-phagy and endolysosomal routes to suppress SERINC5. These findings expand the functional repertoire of RETREG1 in autophagy, identify that retroviruses repurpose micro-ER-phagy to circumvent SERINC5-mediated restriction, and reveal ER-phagy as an understudied battleground in the ongoing arms race between cellular restriction factors and viral accessory proteins. Show less
The objective is to review the newer pharmacological interventions for obesity, specifically single, dual and triple incretin receptor agonists that are either available or in the pipeline for treatme Show more
The objective is to review the newer pharmacological interventions for obesity, specifically single, dual and triple incretin receptor agonists that are either available or in the pipeline for treatment of obesity. The three incretin receptor targets are glucagon like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP) and glucagon. There are several approved single or dual incretin agonists which can be administered subcutaneously daily (e.g., liraglutide) or weekly (e.g., semaglutide, dulaglutide, and exenatide QW), and other experimental dual or triple incretin agonists. Analogues of amylin, peptide YY and oxyntomodulin, as well as the combination of a GLP1R agonist and GIPR antagonist also are in development. Oral semaglutide (administered daily) is approved for type 2 diabetes mellitus and is on track for regulatory review for obesity. The review includes specifically perspectives on the effects of these mechanisms and pharmacological agents on gastric emptying, which contribute to satiation and weight loss, in addition to the established evidence on effects on central mechanisms controlling appetite. In the future, it is anticipated that small molecule GLP-1 receptor agonists (e.g., oral danuglipron) will be developed for treating obesity. These pharmacological agents are having significant impact on glycaemic control and obesity and on their co-morbidities. Show less
Heterozygous variants in the leptin-melanocortin pathway are associated with obesity. However, their effect on the long-term outcomes after Roux-en-Y gastric bypass (RYGB) is still unknown. In this ma Show more
Heterozygous variants in the leptin-melanocortin pathway are associated with obesity. However, their effect on the long-term outcomes after Roux-en-Y gastric bypass (RYGB) is still unknown. In this matched case-control study, 701 participants from the Mayo Clinic Biobank with a history of RYGB were genotyped. Sixty-three patients had a heterozygous variant in the leptin-melanocortin pathway. After excluding patients with potential confounders, carriers were randomly matched (on sex, age, body mass index [BMI], and years since surgery) with two non-carrier controls. The electronic medical record of carriers and matched non-carriers was reviewed for up to 15 years after RYGB. A total of 50 carriers and 100 matched non-carriers with a history of RYGB were included in the study. Seven different genes (LEPR, PCSK1, POMC, SH2B1, SRC1, MC4R, and SIM1) in the leptin-melanocortin pathway were identified. At the time of surgery, the mean age was 50.8 ± 10.6 years, BMI 45.6 ± 7.3 kg/m Carriers of a heterozygous variant in the leptin-melanocortin pathway have a progressive and significant weight regain in the mid- and long-term after RYGB. Genotyping patients experiencing significant weight regain after RYGB could help implement multidisciplinary and individualized weight loss interventions to improve weight maintenance after surgery. Show less