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Updated: Apr 19, 2026
Myeloid Innate Signaling Pathway Regulation by MALT1 Paracaspase Activity
Published on: January 7, 2019
Probes to monitor activity of the paracaspase MALT1
Janna Hachmann1, Laura E Edgington-Mitchell2, Marcin Poreba3
1Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA; Graduate School of Biomedical Sciences, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
Abstract:
The human paracaspase mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) plays a central role in nuclear factor-κB (NF-κB) signaling as both a protease and scaffolding protein. Knocking out MALT1 leads to impaired NF-κB signaling and failure to mount an effective immune response. However, it is unclear to which degree it is the scaffolding function versus the proteolytic activity of MALT1 that is essential. Previous work involving a MALT1 inhibitor with low selectivity suggests that the enzymatic function plays an important role in different cell lines. To help elucidate this proteolytic role of MALT1, we have designed activity-based probes that inhibit its proteolytic activity. The probes selectively label active enzyme and can be used to inhibit MALT1 and trace its activity profile, helping to create a better picture of the significance of the proteolytic function of MALT1.
Insights
Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is crucial for immune responses. New activity-based probes selectively inhibit and trace MALT1
Area of Science:
- Immunology
- Molecular Biology
- Biochemistry
Background:
- The human paracaspase MALT1 is essential for NF-κB signaling, acting as both a protease and scaffolding protein.
- MALT1 knockout impairs immune responses, but the relative importance of its scaffolding versus proteolytic functions remains unclear.
- Previous studies using non-selective inhibitors suggest MALT1's enzymatic activity is critical.
Purpose of the Study:
- To elucidate the specific role of MALT1's proteolytic activity in immune signaling.
- To develop tools for selectively inhibiting and profiling MALT1 protease activity.
- To better understand the significance of MALT1's enzymatic function in biological processes.
Main Methods:
- Design and synthesis of novel activity-based probes targeting MALT1's proteolytic activity.
- Selective labeling of active MALT1 enzyme using these probes.
- Inhibition of MALT1 enzymatic function via activity-based probes.
- Tracing the activity profile of MALT1 in relevant biological systems.
Main Results:
- Development of selective activity-based probes for MALT1.
- Demonstration of probe-mediated inhibition of MALT1 proteolytic activity.
- Successful labeling and profiling of active MALT1 enzyme.
- Establishment of a method to investigate the significance of MALT1's protease function.
Conclusions:
- Activity-based probes provide a valuable tool for studying MALT1's proteolytic function.
- These probes enable selective inhibition and activity profiling, aiding in understanding MALT1's role.
- The findings contribute to a clearer picture of the significance of MALT1's enzymatic activity in immune signaling and disease.
