New Insights Into Human Hyaluronidase 4/Chondroitin Sulphate Hydrolase

Abstract

In this review, the current experimental evidence, literature and hypotheses surrounding hyaluronidase 4 [HYAL4, also known as chondroitin sulphate hydrolase (CHSE)] and chondroitin sulphate (CS) are explored. Originally named for its sequence similarity to other members of the hyaluronidase family, HYAL4 is actually a relatively distinct member of the family, particularly for its unique degradation of CS-D (2-O-, 6-O-sulphated CS) motifs and specific expression. Human HYAL4 protein expression and structural features are discussed in relation to different isoforms, activities, potential localisations and protein-protein interaction partners. CS proteoglycan targets of HYAL4 activity include: serglycin, aggrecan, CD44 and sulfatase 2, with other potential proteoglycans yet to be identified. Importantly, changes in HYAL4 expression changes in human disease have been described for testicular, bladder and kidney cancers, with gene mutations reported for several others including: leukaemia, endometrial, ovarian, colorectal, head and neck, stomach, lung and breast cancers. The HYAL4 gene also plays a role in P53 negative human cancer cell proliferation and is linked to stem cell naivety. However, its role in cancer remains relatively unexplored. Finally, current tools and techniques for the detection of specific HYAL4 activity in biological samples are critically assessed. Understanding the role of HYAL4 in human diseases will fortify our understanding of developmental processes and disease manifestation, ultimately providing novel diagnostic opportunities and therapeutic targets for drug discovery.

Myocardial Oedema as a Consequence of Viral Infection and Persistence – a Narrative Review with Focus on COVID-19 and Post COVID Sequelae

“…Entry gets facilitated by CD209L, NRP1, TMPRSS2, heparan sulphate, cathepsin B/L and triggers an endothelial inflammatory response [26,182,[219][220][221][222][223]230,259,260]. Viral infection upregulates cytokines production ("cytokine storm") [261], ROS production [262] and enhances the activity of glycocalyx degrading enzymes such as MMPs, heparanases and hyaluronidases [90,91,119,[263][264][265]. Hereby the infection leads to endothelial cell injury, dysfunction and contributes to glycocalyx breakdown [23][24][25][26]182,230,259,260].…”

“…Normally, the glycocalyx is in a balance of constant shedding due to flow and degrading enzymes, and renewal via production of new components [308]. However, during inflammation ROS [262] and the enzymes capable of degrading the glycocalyx such as hyaluronidases [263], heparinases [264] and MMPs [265] exhibit enhanced activity. In addition, there is increased leucocyte adhesion and diapedesis due to endothelial activation and upregulation of cellular adhesion molecules [83].…”

Endothelial Glycocalyx Degradation in Critical Illness and Injury

“…There are 3 known human hydrolases capable of degrading CS outside of lysosomes; SPAM1 (also called PH-20, located mostly in the sperm acrosome), hyaluronidase-1 (see above) and hyaluronidase-4 (30). Hyaluronidase-4, (also called CS hydrolase) has a membrane-bound form present in neutrophils that preferentially hydrolyze CS over HA (30).…”

Spatiotemporal diversity and regulation of glycosaminoglycans in cell homeostasis and human disease

“…Although all three can also cleave hyaluronic acid glycosaminoglycans, HYAL4 is predominantly an endo-β- N -acetylgalactosaminidase that degrades CS motifs containing 2- O and 6- O sulfated subunits (CS-D). HYAL4 has been shown to cleave CS chains on multiple proteoglycans, including serglycin, aggrecan, and CD44, and its expression is altered in certain disease states, such as cancer ( 59 ). Altogether, the activity and expression of biosynthetic enzymes and secreted remodeling factors discussed here have a significant impact on the huge chemical diversity of HS and CS/DS chains and their resultant functions across tissue/cell types and disease states.…”