Generation of active myeloid and lymphoid granule serine proteases requires processing by the granule thiol protease dipeptidyl peptidase I

Michael J. McGuire, Peter E. Lipsky, Dwain L Thiele

Research output: Contribution to journalArticle

173 Citations (Scopus)

Abstract

The proenzyme activation peptides predicted from cDNAs encoding each of the granule serine proteases synthesized by cytotoxic lymphocytes and myeloid and mast cells are composed of 2 residues. The mechanism by which these amino-terminal dipeptides are cleaved to generate the active enzymes has not been elucidated. The comparable distribution of dipeptidyl peptidase I (DPPI) and serine proteases and the ability of DPPI to hydrolyze relevant dipeptide sequences suggested a role for DPPI in the processing and activation of granule serine proteases. This study demonstrates that inhibition of DPPI activity is associated with impairment of the generation of granule serine protease activity in CD8(+) T cells, lymphokine-activated killer cells, P815 mastocytoma cells, and U-937 myeloid cells. Inhibition of DPPI resulted in impairment of the generation of cathepsin G enzymatic activity without reduction in the amount of immunoreactive cathepsin G produced. In U-937 cells pulsed with [3H]isoleucine, inhibition of DPPI activity was associated with the accumulation of the inactive proenzyme form of cathepsin G bearing an amino-terminal dipeptide extension to the isoleucine residue that normally occupies the amino terminus of the enzymatically active protein. These results indicate that DPPI plays a requisite role in the post-translational processing and activation of members of the family of granule serine proteases expressed in bone marrow-derived effector cells.

Original languageEnglish (US)
Pages (from-to)2458-2467
Number of pages10
JournalJournal of Biological Chemistry
Volume268
Issue number4
StatePublished - Feb 5 1993

Fingerprint

Cathepsin C
Serine Proteases
Sulfhydryl Compounds
Peptide Hydrolases
Cathepsin G
Processing
Dipeptides
Enzyme Precursors
Isoleucine
Chemical activation
Myeloid Cells
Bearings (structural)
Mastocytoma
Lymphokine-Activated Killer Cells
Aptitude
T-cells
Lymphocytes
Lymphokines
Mast Cells
Bone

ASJC Scopus subject areas

  • Biochemistry

Cite this

Generation of active myeloid and lymphoid granule serine proteases requires processing by the granule thiol protease dipeptidyl peptidase I. / McGuire, Michael J.; Lipsky, Peter E.; Thiele, Dwain L.

In: Journal of Biological Chemistry, Vol. 268, No. 4, 05.02.1993, p. 2458-2467.

Research output: Contribution to journalArticle

@article{97c77e6fd32744d1a75a742735c31bbd,
title = "Generation of active myeloid and lymphoid granule serine proteases requires processing by the granule thiol protease dipeptidyl peptidase I",
abstract = "The proenzyme activation peptides predicted from cDNAs encoding each of the granule serine proteases synthesized by cytotoxic lymphocytes and myeloid and mast cells are composed of 2 residues. The mechanism by which these amino-terminal dipeptides are cleaved to generate the active enzymes has not been elucidated. The comparable distribution of dipeptidyl peptidase I (DPPI) and serine proteases and the ability of DPPI to hydrolyze relevant dipeptide sequences suggested a role for DPPI in the processing and activation of granule serine proteases. This study demonstrates that inhibition of DPPI activity is associated with impairment of the generation of granule serine protease activity in CD8(+) T cells, lymphokine-activated killer cells, P815 mastocytoma cells, and U-937 myeloid cells. Inhibition of DPPI resulted in impairment of the generation of cathepsin G enzymatic activity without reduction in the amount of immunoreactive cathepsin G produced. In U-937 cells pulsed with [3H]isoleucine, inhibition of DPPI activity was associated with the accumulation of the inactive proenzyme form of cathepsin G bearing an amino-terminal dipeptide extension to the isoleucine residue that normally occupies the amino terminus of the enzymatically active protein. These results indicate that DPPI plays a requisite role in the post-translational processing and activation of members of the family of granule serine proteases expressed in bone marrow-derived effector cells.",
author = "McGuire, {Michael J.} and Lipsky, {Peter E.} and Thiele, {Dwain L}",
year = "1993",
month = "2",
day = "5",
language = "English (US)",
volume = "268",
pages = "2458--2467",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "4",

}

TY - JOUR

T1 - Generation of active myeloid and lymphoid granule serine proteases requires processing by the granule thiol protease dipeptidyl peptidase I

AU - McGuire, Michael J.

AU - Lipsky, Peter E.

AU - Thiele, Dwain L

PY - 1993/2/5

Y1 - 1993/2/5

N2 - The proenzyme activation peptides predicted from cDNAs encoding each of the granule serine proteases synthesized by cytotoxic lymphocytes and myeloid and mast cells are composed of 2 residues. The mechanism by which these amino-terminal dipeptides are cleaved to generate the active enzymes has not been elucidated. The comparable distribution of dipeptidyl peptidase I (DPPI) and serine proteases and the ability of DPPI to hydrolyze relevant dipeptide sequences suggested a role for DPPI in the processing and activation of granule serine proteases. This study demonstrates that inhibition of DPPI activity is associated with impairment of the generation of granule serine protease activity in CD8(+) T cells, lymphokine-activated killer cells, P815 mastocytoma cells, and U-937 myeloid cells. Inhibition of DPPI resulted in impairment of the generation of cathepsin G enzymatic activity without reduction in the amount of immunoreactive cathepsin G produced. In U-937 cells pulsed with [3H]isoleucine, inhibition of DPPI activity was associated with the accumulation of the inactive proenzyme form of cathepsin G bearing an amino-terminal dipeptide extension to the isoleucine residue that normally occupies the amino terminus of the enzymatically active protein. These results indicate that DPPI plays a requisite role in the post-translational processing and activation of members of the family of granule serine proteases expressed in bone marrow-derived effector cells.

AB - The proenzyme activation peptides predicted from cDNAs encoding each of the granule serine proteases synthesized by cytotoxic lymphocytes and myeloid and mast cells are composed of 2 residues. The mechanism by which these amino-terminal dipeptides are cleaved to generate the active enzymes has not been elucidated. The comparable distribution of dipeptidyl peptidase I (DPPI) and serine proteases and the ability of DPPI to hydrolyze relevant dipeptide sequences suggested a role for DPPI in the processing and activation of granule serine proteases. This study demonstrates that inhibition of DPPI activity is associated with impairment of the generation of granule serine protease activity in CD8(+) T cells, lymphokine-activated killer cells, P815 mastocytoma cells, and U-937 myeloid cells. Inhibition of DPPI resulted in impairment of the generation of cathepsin G enzymatic activity without reduction in the amount of immunoreactive cathepsin G produced. In U-937 cells pulsed with [3H]isoleucine, inhibition of DPPI activity was associated with the accumulation of the inactive proenzyme form of cathepsin G bearing an amino-terminal dipeptide extension to the isoleucine residue that normally occupies the amino terminus of the enzymatically active protein. These results indicate that DPPI plays a requisite role in the post-translational processing and activation of members of the family of granule serine proteases expressed in bone marrow-derived effector cells.

UR - http://www.scopus.com/inward/record.url?scp=0027518670&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0027518670&partnerID=8YFLogxK

M3 - Article

VL - 268

SP - 2458

EP - 2467

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 4

ER -