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The role of extracellular Granzyme b in cytotoxic Lymphocyte migration
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posted on 15.02.2017by Prakash, Monica Devi
Granzyme B (GrB) is a known intracellular cytotoxin that has also been shown to cleave
extracellular substrates. GrB is detectable in extracellular fluids under normal, healthy
conditions and its levels increase in many disease states that are associated with cytotoxic
lymphocyte (eL) hyperactivity. Until now, the role of extracellular GrB has gone unexplained.
Among the known extracellular substrates of GrB are several ECM proteins, cleavage of
which leads to cell detachment and potential anoikis. Based on the known expression and
substrates of GrB, it was hypothesised that extracellular GrB is derived from CLs, which release
GrB to degrade extracellular matrix proteins and facilitate cell migration into target tissues.
This study showed that zymogen and active forms of GrB are constitutively secreted
from CLs, by both conventional and non-conventional pathways. It was subsequently shown
that in the absence of GrB, or upon perturbation of its secretion/activity, CLs exhibit a cellautonomous defect in migration through basement membranes in vitro, and in homing to sites of
inflammation and infection in vivo. No such defect was evident during interstitial migration.
Using a proteomics-iJased approach, it was also demonstrated that GrB cleaves several
components of the basement membrane in the context of a complex matrix.
The proposed model requires GrB to be released by CLs upon exit from the vasculature
(extravasation) and entry to target tissues to break down the basement membrane lining each
compartment. This process was previously believed to be predominantly mediated by matrix
metalloproteinases, but the studies here reveal the significant contribution made by GrB, and
highlight the broader nature of granzyme function.