Preventing MALT1-mediated CYLD cleavage induces intestinal dysbiosis and reduces EAE severity

Area of Science:

• Immunology
• Molecular Biology
• Cancer Research

Background:

• The paracaspase MALT1 is crucial for lymphocyte activation and immune signaling.
• MALT1 protease activity is a therapeutic target, but broad inhibition causes inflammation.
• Understanding MALT1 substrate-specific effects is vital for safe therapeutic strategies.

Purpose of the Study:

• To investigate the in vivo effects of blocking a single MALT1 substrate cleavage.
• To assess the therapeutic potential of targeting MALT1 substrate CYLD cleavage.

Main Methods:

• Generation of CYLD(R321A) knock-in mice resistant to MALT1 cleavage.
• Analysis of lymphocyte development, immune signaling, and spontaneous inflammation in knock-in mice.
• Evaluation of gut microbiota composition and disease severity in a multiple sclerosis model.

Main Results:

• CYLD(R321A) mice are healthy with normal lymphocyte function and no spontaneous inflammation.
• Blocking MALT1 cleavage of CYLD alters gut microbiota composition.
• MALT1 inhibition via CYLD resistance reduces disease severity in a multiple sclerosis model.

Conclusions:

• Blocking cleavage of the single MALT1 substrate CYLD is sufficient to modulate microbiota and neuroinflammation.
• This approach avoids lymphocyte defects and multiorgan inflammation seen with broad MALT1 inhibition.
• Substrate-specific MALT1 targeting represents a refined and safer therapeutic strategy.