Siamese Twins: The Multimodular Mechanisms of Golgi Maturation and Glycan Synthesis Are Coupled at Their Core.

The Golgi apparatus functions as the central processing hub for proteins and lipids, orchestrating glycosylation, sorting, and secretion. Once viewed as a passive site of bulk enzyme recycling, the Golgi is now recognized as a highly dynamic, multimodular system in which intra-Golgi trafficking and glycan synthesis operate as tightly interdependent "Siamese twins." The classical cisternal maturation model, initially based on uniform COPI-mediated recycling, has evolved into the multimodular cisternal maturation (MCM) framework, revealing the coexistence of multiple, specialized recycling modules. Distinct sets of glycosyltransferases form coherent enzymatic modules, each maintained by dedicated retrograde pathways-some COPI-dependent, others COPI-independent-that ensure compartmental fidelity and enable differential regulation of glycan synthesis. These pathways are coordinated by adaptors, retainers, and lipid identity cues that collectively sustain Golgi polarity and adaptability to cellular and metabolic states. Disruption of this modular recycling logic leads to enzyme mislocalization, defective glycosylation, and disease, ranging from congenital disorders of glycosylation to oncogenic transformation. The transition from bulk to multimodular recycling thus redefines the Golgi as an integrated regulatory platform linking membrane trafficking to metabolic and signaling networks.