Ouidja Mohand Ouidir, Biard Denis S F, Huynh Minh Bao, Laffray Xavier, Gomez-Henao Wilton, Chantepie Sandrine, Le Douaron Gael, Rebergue Nicolas, Maïza Auriane, Merrick Heloise, De Lichy Aubert, Dady Alwyn, González-Velasco Oscar, Rubio Karla, Barreto Guillermo, Baranger Kévin, Cormier-Daire Valerie, De Las Rivas Javier, Fernig David G, Papy-Garcia Dulce
Univ Paris Est Creteil, Glycobiology, Cell Growth and Tissue Repair Research Unit (Gly-CRRET), Creteil, France.
CEA, Institut de Biologie François Jacob (IBFJ), SEPIA, Université Paris-Saclay, Fontenay-aux-Roses, France.
Essays Biochem. 2024 Dec 4;68(4):555-578. doi: 10.1042/EBC20240106.
Heparan sulfate (HS) and chondroitin sulfate (CS) proteoglycans (PG) consist of a core protein to which the glycosaminoglycan (GAG) chains, HS or CS, are attached through a common linker tetrasaccharide. In the extracellular space, they are involved in the regulation of cell communication, assuring development and homeostasis. The HSPG biosynthetic pathway has documented 51 genes, with many diseases associated to defects in some of them. The phenotypic consequences of this genetic variation in humans, and of genetic ablation in mice, and their expression patterns, led to a phenotypically centered HSPG biosynthetic pathway model. In this model, HS sequences produced by ubiquitous NDST1, HS2ST and HS6ST enzymes are essential for normal development and homeostasis, whereas tissue restricted HS sequences produced by the non-ubiquitous NDST2-4, HS6ST2-3, and HS3ST1-6 enzymes are involved in adaptative behaviors, cognition, tissue responsiveness to stimuli, and vulnerability to disease. The model indicates that the flux through the HSPG/CSPG pathways and its diverse branches is regulated by substrate preferences and protein-protein-interactions. This results in a privileged biosynthesis of HSPG over that of CSPGs, explaining the phenotypes of linkeropathies, disease caused by defects in genes involved in the biosynthesis of the common tetrasaccharide linker. Documented feedback loops whereby cells regulate HS sulfation, and hence the interactions of HS with protein partners, may be similarly implemented, e.g., protein tyrosine sulfation and other posttranslational modifications in enzymes of the HSPG pathway. Together, ubiquitous HS, specialized HS, and their biosynthesis model can facilitate research for a better understanding of HSPG roles in physiology and pathology.
硫酸乙酰肝素（HS）和硫酸软骨素（CS）蛋白聚糖（PG）由一个核心蛋白组成，糖胺聚糖（GAG）链，即HS或CS，通过一个共同的连接四糖连接到该核心蛋白上。在细胞外空间，它们参与细胞通讯的调节，确保发育和体内平衡。HSPG生物合成途径已记录有51个基因，许多疾病与其中一些基因的缺陷有关。这种人类基因变异、小鼠基因敲除的表型后果及其表达模式，导致了一个以表型为中心的HSPG生物合成途径模型。在这个模型中，由普遍存在的NDST1、HS2ST和HS6ST酶产生的HS序列对于正常发育和体内平衡至关重要，而由非普遍存在的NDST2 - 4、HS6ST2 - 3和HS3ST1 - 6酶产生的组织特异性HS序列则参与适应性行为、认知、组织对刺激的反应以及对疾病的易感性。该模型表明，通过HSPG/CSPG途径及其不同分支的通量受底物偏好和蛋白质 - 蛋白质相互作用的调节。这导致了HSPG相对于CSPG的优先生物合成，解释了连接病的表型，连接病是由参与共同四糖连接生物合成的基因缺陷引起的疾病。细胞调节HS硫酸化，进而调节HS与蛋白质伴侣相互作用的已记录反馈回路可能同样存在，例如，蛋白质酪氨酸硫酸化和HSPG途径中酶的其他翻译后修饰。总之，普遍存在的HS、特殊的HS及其生物合成模型有助于开展研究，以更好地理解HSPG在生理和病理中的作用。
