Unveiling the Biological Role of Serglycin Proteoglycans Studies on Serglycin Knock-Out Mice

Serglycin (SG) proteoglycans (PG) are predominantly located intracellularly in secretory vesicles of hematopoietic cells such as macrophages, cytotoxic T lymphocytes (CTLs), monocytes, basophils, neutrophils and mast cells (MCs). These PGs are characterized by their protease-resistant serine and glycine-rich core and also by their covalently attached negatively charged glycosaminoglycans (GAG) chains. We showed that SG PGs are the dominant PGs species in CTLs where they contributed to proper sub-structural organization of the secretory vesicles. Furthermore, different granule-specific components exhibited distinct SG PG dependence for storage, where granzyme B levels were shown to be highly affected, while granzyme A or perforin levels were not. MCs are important immune cells that release preformed mediators upon activation. We confirmed that SG PGs are the major PG species in mucosal-like bone marrow-derived MCs (BMMCs) and their absence leads to defects in the granule organization and inability to store specific granule components (mMCP-5, CPA). However, mMCP-1 and mMCP-7 are not dependent on SG for storage. SG-dependent granule compounds exert many functions in homeostasis and interactions between immune cells. We noted that older SG animals spontaneously developed enlarged peripheral lymphoid organs, namely the spleen and Peyer’s patches. Additionally, investigations of the spleen cell population from SG revealed an increased population of CD45RC expressing cells but a reduction in CD4 positive cells. Sorting of SG PGs into secretory vesicles is a poorly understood process. We showed that in the presence of a reducing agent, granules in SG BMMCs show a striking resemblance to those found in SG cells lacking a defined granular organization. Moreover, CPA’s storage was shown to be affected by the presence of the reducing agent, possibly due to its interaction with intra-granular SG PGs.