Gram-negative bacteria build their cell envelope by transporting various sugar-based precursors across the inner membrane on the shared lipid carrier undecaprenyl (also known as C55). Because the cell...

Gram-negative bacteria build their cell envelope by transporting various sugar-based precursors across the inner membrane on the shared lipid carrier undecaprenyl (also known as C55). Because the cellular pool of undecaprenyl is finite and used by multiple competing pathways, it must be efficiently regenerated to sustain envelope assembly. Yet the enzymes that release polysaccharide cargo from the lipid carrier have remained elusive, leaving a major gap in our understanding of bacterial envelope biogenesis. Here we identify three periplasmic enzymes in Escherichia coli - UprA, UprB, and UprC - that hydrolyze the bond linking polysaccharide precursors to undecaprenyl. UprA releases elongating peptidoglycan glycan strands from the inner membrane, catalyzing the long-sought terminal step of peptidoglycan synthesis. UprB cleaves the undecaprenyl-linked initiating unit common to the enterobacterial common antigen and O-antigen pathways, while UprC is the likely release factor for the colanic acid pathway. These enzymes define a widespread Upr-like protein family (formerly DUF218) as polysaccharide release factors, revealing a unifying mechanism by which bacteria coordinate envelope assembly. Because all three Upr-like proteins share a conserved catalytic core, this family represents a potential target for antibiotics that simultaneously disrupt multiple envelope pathways. ### Competing Interest Statement The authors have declared no competing interest. F.R.S.-FNRS, WELBIO X.1509.24, ARC 22/27-128, Chargé de Recherche, FRIA European Molecular Biology Organization, https://ror.org/04wfr2810, ALTF 359-2023 Agence Nationale de la Recherche, https://ror.org/00rbzpz17, ANR-20-CE44-0009-01, ANR-20-PAMR-0010

Transporting molecules across biological membranes is essential for life. In nature, this can occur through passive transport, known as diffusion.

The lymphatic system plays a central role in lipid absorption by transporting triglyceride-rich particles called chylomicrons (CMs) from the small intestine to the systemic circulation. However, the molecular mechanism by which CMs get into the intestinal lymphatics is unknown. Here, we demonstrated that GPR182, an atypical chemokine receptor in lymphatic endothelial cells, mediates dietary fat absorption. GPR182-KO mice exhibited a selective increase in circulating high-density lipoproteins and are resistant to diet-induced obesity. GPR182 ablation in mice led to poor lipid absorption and thereby a delay in growth during development. GPR182 broadly interacted with and transported lipoproteins. Transmission electron microscopy analysis revealed that, mechanistically, loss of GPR182 prevented CMs from entering the lacteal lumen of the small intestine. Consistent with this, GPR182 blockade with mAbs protected mice from diet-induced obesity and treated existing obesity. Together, our study identifies GPR182 as a lipoprotein receptor that mediates dietary fat absorption and supports GPR182 blockade as a feasible approach to treating obesity and related disorders.

Historically, research on chylomicron entry into intestinal lymphatic vessels (lacteals) has been polarized between paracellular and transcellular transport models. In this issue of the JCI, Sun et al. identified GPR182 as a lipoprotein receptor in lymphatic endothelial cells (LECs), profoundly advancing our understanding of intestinal lipid absorption. They observed poor fat absorption in GPR182-deficient mice and demonstrated the role of GPR182 in transporting chylomicrons across the LECs into the lacteal lumen. This discovery establishes a molecular basis for transcellular transport of chylomicrons, challenging the traditional view that lacteal lipid entry is predominantly paracellular. By linking receptor-mediated uptake to impaired fat absorption and protection against fat-induced obesity and steatosis, this study expands the biological and translational implications of lacteal transport. Consequently, rather than favoring a single model, future research should investigate the integration of both paracellular and transcellular transport models in vivo.

Transmembrane transport of the nucleotides cAMP (cyclic adenosine monophosphate) and AMP (adenosine monophosphate) is challenging, but can be achieved using a two-component system consisting of a syn...

Migrating freshwater eels depend on the mobilisation of stored lipids to successfully arrive at their distant spawning locations. As 11-ketotestosterone (11KT) can increase the lipid-transporting capa...

Autoimmunity's Hidden Trigger: Antibodies Against a Lipid Carrier A recent commentary in Clinical Chemistry highlights a novel autoimmune mechanism behind severe hypertriglyceridemia. The condition, often linked to metabolic disorders, can in rare cases be driven by autoantibodies targeting GPIHBP1, a protein crucial for transporting lipoprotein lipase. This enzyme is essential for breaking down triglyceride-rich lipoproteins in the bloodstream. The commentary synthesizes data from several cohort studies, revealing that the prevalence of these autoantibodies ranges from approximately 1% to 15% in highly selected patient groups with unexplained or severe hypertriglyceridemia.

Delivery of mRNA (mRNA) to the central nervous system (CNS) remains a significant challenge. Herein, we design a library of furan-derived lipids and, to our knowledge, for the first time, leverage the...

In the relentless pursuit to unravel the complex mechanisms underlying Alzheimer’s disease, a groundbreaking study has emerged, illuminating the nuanced role of apolipoprotein E (APOE) isoforms in shaping the microglial environment within the brain. These immune cells, pivotal in maintaining neural homeostasis, respond intricately to the genetic variants of APOE, a lipid-transporting protein long implicated in Alzheimer’s risk modulation. The recent research conducted by Murphy, Hu, Wolfs, and colleagues, published in…

Lipid transport proteins (LTPs) facilitate non-vesicular lipid exchange between cellular compartments and have critical roles in lipid homeostasis. A recently identified family of bridge-like LTPs (BLTPs) is thought to form lipid-transporting conduits between organelles. One of these, BLTP2, is conserved across species but its function is not known. Here we show that BLTP2 regulates plasma membrane (PM) fluidity by increasing phosphatidylethanolamine (PE) levels in the PM. BLTP2 localizes to endoplasmic reticulum (ER)–PM contact sites, and transports PE in vivo, suggesting it drives PE movement from ER to PM. We find that BLTP2 works in parallel with another pathway that regulates intracellular PE distribution and PM fluidity. BLTP2 expression correlates with breast cancer aggressiveness. We found that BLTP2 facilitates growth of a triple negative breast cancer cell line and sustains its aggressiveness in an in vivo model of metastasis, suggesting maintenance of PM fluidity by BLTP2 ma

Covill-Cooke et al. find that the ERMES lipid-transporting complex, long-thought to be an obligate heterotetramer, can be replaced by only one component: m