MALT1 Protease Activity Controls the Expression of Inflammatory Genes in Keratinocytes upon Zymosan Stimulation

Anja Schmitt; Paula Grondona; Tabea Maier; Marc Brändle; Caroline Schönfeld; Günter Jäger; Corinna Kosnopfel; Franziska C Eberle; Birgit Schittek; Klaus Schulze-Osthoff; Amir S Yazdi; Stephan Hailfinger

doi:10.1016/j.jid.2015.12.027

MALT1 Protease Activity Controls the Expression of Inflammatory Genes in Keratinocytes upon Zymosan Stimulation

J Invest Dermatol. 2016 Apr;136(4):788-797. doi: 10.1016/j.jid.2015.12.027. Epub 2016 Jan 6.

Affiliations

¹ Interfaculty Institute for Biochemistry, Eberhard Karls University of Tuebingen, Tuebingen, Germany.
² Department of Dermatology, Eberhard Karls University of Tuebingen, Tuebingen, Germany.
³ Institute of Medical Genetics and Applied Genomics, Eberhard Karls University of Tuebingen, Tuebingen, Germany.
⁴ Interfaculty Institute for Biochemistry, Eberhard Karls University of Tuebingen, Tuebingen, Germany. Electronic address: Stephan.Hailfinger@uni-tuebingen.de.

PMID: 26767426
DOI: 10.1016/j.jid.2015.12.027

Abstract

The protease activity of the paracaspase mucosa-associated lymphoid tissue lymphoma translocation gene 1 (MALT1) plays an important role in antigen receptor-mediated lymphocyte activation by controlling the activity of the transcription factor nuclear factor-κB and is thus essential for the expression of inflammatory target genes. MALT1 is not only present in cells of the hematopoietic lineage, but is ubiquitously expressed. Here we report that stimulation with zymosan or Staphylococcus aureus induced MALT1 protease activity in human primary keratinocytes. Inhibition of the Src family of kinases or novel protein kinase C isoforms as well as silencing of CARMA2 or BCL10 interfered with activation of MALT1 protease. Silencing or inhibition of MALT1 protease strongly decreased the expression of important inflammatory genes such as TNFα, IL-17C, CXCL8 and HBD-2. MALT1-inhibited cells were unable to mount an antimicrobial response upon zymosan stimulation or phorbolester/ionomycin treatment, demonstrating a central role of MALT1 protease activity in keratinocyte immunity and suggesting MALT1 as a potential target in inflammatory skin diseases.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing / genetics
Adaptor Proteins, Signal Transducing / metabolism
Anti-Infective Agents / chemistry
B-Cell CLL-Lymphoma 10 Protein
CARD Signaling Adaptor Proteins / genetics
CARD Signaling Adaptor Proteins / metabolism
Caspases / genetics
Caspases / metabolism*
Gene Expression Profiling
Gene Silencing
Guanylate Cyclase / genetics
Guanylate Cyclase / metabolism
Humans
Inflammation / genetics*
Interleukin-17 / genetics
Interleukin-17 / metabolism
Interleukin-8 / genetics
Interleukin-8 / metabolism
Keratinocytes / cytology*
Keratinocytes / drug effects
Membrane Proteins / genetics
Membrane Proteins / metabolism
Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein
NF-kappa B p50 Subunit / genetics
NF-kappa B p50 Subunit / metabolism
Neoplasm Proteins / genetics
Neoplasm Proteins / metabolism*
Oligonucleotide Array Sequence Analysis
Protein Isoforms
Protein Kinase C / metabolism
Staphylococcus aureus
Tumor Necrosis Factor-alpha / genetics
Tumor Necrosis Factor-alpha / metabolism
Zymosan / chemistry*
beta-Defensins / genetics
beta-Defensins / metabolism
src-Family Kinases / metabolism

Substances

Adaptor Proteins, Signal Transducing
Anti-Infective Agents
B-Cell CLL-Lymphoma 10 Protein
BCL10 protein, human
CARD Signaling Adaptor Proteins
CXCL8 protein, human
DEFB4A protein, human
IL17C protein, human
Interleukin-17
Interleukin-8
Membrane Proteins
NF-kappa B p50 Subunit
NFKB1 protein, human
Neoplasm Proteins
Protein Isoforms
Tumor Necrosis Factor-alpha
beta-Defensins
Zymosan
src-Family Kinases
Protein Kinase C
Caspases
MALT1 protein, human
Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein
CARD14 protein, human
Guanylate Cyclase