Anita Nasrallah

The Golgi complex serves as the central hub of the biosynthetic pathway, where anterograde and retrograde trafficking converge. How cargo and Golgi-resident proteins traverse this organelle has long been debated. Recent studies have identified a molecular machinery that sorts resident proteins into retrograde-directed COPI vesicles during cisternal maturation. Golgi phosphoprotein 3 (GOLPH3) is a key component of this system; however, its physiological relevance and regulatory mechanisms remain poorly defined. Here, we show that GOLPH3 depletion in mice alters both protein and lipid glycosylation, causes partially penetrant embryonic lethality, and severely impairs growth and bone mineralization. At the molecular level, we find that GOLPH3 is regulated by functionally antagonistic S-acylation events that control the topology of its membrane association. To mediate retrograde trafficking of Golgi-resident glycosyltransferases, GOLPH3 must bind their cytosolic tails. This occurs via a negatively charged surface region, which is correctly oriented only in one of the S-acylated GOLPH3 conformations. Together, these findings reveal a lipid-mediated regulatory mechanism for intra-Golgi trafficking and establish the critical role of GOLPH3 in vertebrate development.

Lipids are fundamental components of the brain, crucial for synaptic transmission and signal propagation. Altered brain lipid composition is associated with common and rare neuropathologies, yet, the spatial organization of the mammalian brain lipidome remains insufficiently characterized compared to other modalities. Here, we mapped the membrane lipid architecture of the adult mouse brain at micrometric scale, across sexes, and during pregnancy. This Lipid Brain Atlas reveals that lipids define a fine-grained biochemical structure that aligns with functional anatomy. Membrane lipid spatial heterogeneity clusters into territories, which we termed lipizones. Lipizones partially mirror cell type territories, but also capture distal axon terminals. Through lipizones, (i) we reveal the organizing principles of the gray matter lipidome, related to connectivity and cytoarchitecture; (ii) we discover a new axis of oligodendrocyte heterogeneity in the white matter; (iii) and we find biochemical zonation in the choroid plexus and in the ventricular walls. We show that this lipidomic architecture can adapt to changing physiological needs. In the brain of pregnant females, the white matter is metabolically activated and the outer cortex is reorganized. These results are a foundational resource (https://lbae-v2.epfl.ch/), poised to reshape our understanding of lipids in brain development, physiology, and pathology.