Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:3.4.21.37 (
neutrophil elastase
)
4,078
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Proteolytic processing is an irreversible post-translational modification functioning as a ubiquitous regulator of cellular activity. Protease activity is tightly regulated via control of gene expression, enzyme and substrate compartmentalization, zymogen activation, enzyme inactivation, and substrate availability. Emerging evidence suggests that proteolysis can also be regulated by substrate glycosylation and that glycosylation of individual sites on a substrate can decrease or, in rare cases, increase its sensitivity to proteolysis. Here, we investigated the relationship between site-specific, mucin-type (or GalNAc-type)
O
-glycosylation and proteolytic cleavage of extracellular proteins. Using
in silico
analysis, we found that
O
-glycosylation and cleavage sites are significantly associated with each other. We then used a positional proteomic strategy, terminal amine isotopic labeling of substrates (TAILS), to map the
in vivo
cleavage sites in HepG2 SimpleCells with and without one of the key initiating GalNAc transferases,
GalNAc-T2
, and after treatment with exogenous matrix metalloproteinase 9 (MMP9) or
neutrophil elastase
. Surprisingly, we found that
loss
of
GalNAc-T2
not only increased cleavage, but also decreased cleavage across a broad range of other substrates, including key regulators of the protease network. We also found altered processing of several central regulators of lipid homeostasis, including apolipoprotein B and the phospholipid transfer protein, providing new clues to the previously reported link between
GALNT2
and lipid homeostasis. In summary, we show that loss of
GalNAc-T2
O
-glycosylation leads to a general decrease in cleavage and that
GalNAc-T2
O
-glycosylation affects key regulators of the cellular proteolytic network, including multiple members of the serpin family.
...
PMID:TAILS N-terminomics and proteomics reveal complex regulation of proteolytic cleavage by
O
-glycosylation. 2959 93
