Normal lymphocyte homeostasis and function in MALT1 protease-resistant HOIL-1 knock-in mice.

The uniqueness of MALT1 protease activity in controlling several aspects of immunity in humans has made it a very attractive therapeutic target for multiple autoimmune diseases and lymphoid malignancies. Despite several encouraging preclinical studies with MALT1 inhibitors, severe reduction in regulatory T cells and immune-mediated pathology seen in MALT1 protease-dead (MALT1-PD) mice and some, but not all, studies analysing the effect of prolonged pharmacological MALT1 protease inhibition, indicates the need to further unravel the mechanism of MALT1 protease function. Notably, the contribution of individual MALT1 substrates to the immune defects seen in MALT1-PD mice is still unclear.

Clinical Relevance of Serum Kyn/Trp Ratio and Basal and IFNγ-Upregulated IDO1 Expression in Peripheral Monocytes in Early Stage Melanoma.

Immune escape is an early phenomenon in cancer development/progression. Indoleamine 2,3-dioxygenase 1 (IDO1) is a normal endogenous mechanism of acquired peripheral immune tolerance and may therefore be tumor-promoting. This study investigated the clinical relevance of IDO1 expression by immune cells in the lymph nodes and blood and of the serum kynurenine/tryptophan (Kyn/Trp) ratio in 65 systemic treatment naïve stage I-III melanoma patients.

Immune Monitoring in Melanoma and Urothelial Cancer Patients Treated with Anti-PD-1 Immunotherapy and SBRT Discloses Tumor Specific Immune Signatures.

(1) Background: Blockade of the PD-1/PD-L1 pathway has revolutionized the oncology field in the last decade. However, the proportion of patients experiencing a durable response is still limited. In the current study, we performed an extensive immune monitoring in patients with stage III/IV melanoma and stage IV UC who received anti-PD-1 immunotherapy with SBRT.

Analysis of T cells in mouse lymphoid tissue and blood with flow cytometry.

T cells play a key role in adaptive immunity. Defects in specific T cell receptors or signaling proteins can alter their frequency and activation status, which may be associated with immune disease or cancer. Monitoring of T cell frequency and function in genetically modified mice or murine models of disease is therefore of high interest.

Long-Term MALT1 Inhibition in Adult Mice Without Severe Systemic Autoimmunity.

The protease MALT1 is a key regulator of NF-κB signaling and a novel therapeutic target in autoimmunity and cancer. Initial enthusiasm supported by preclinical results with MALT1 inhibitors was tempered by studies showing that germline MALT1 protease inactivation in mice results in reduced regulatory T cells and lethal multi-organ inflammation due to expansion of IFN-γ-producing T cells. However, we show that long-term MALT1 inactivation, starting in adulthood, is not associated with severe systemic inflammation, despite reduced regulatory T cells.

MALT1-Deficient Mice Develop Atopic-Like Dermatitis Upon Aging.

MALT1 plays an important role in innate and adaptive immune signaling by acting as a scaffold protein that mediates NF-κB signaling. In addition, MALT1 is a cysteine protease that further fine tunes proinflammatory signaling by cleaving specific substrates. Deregulated MALT1 activity has been associated with immunodeficiency, autoimmunity, and cancer in mice and humans.

MALT1 Proteolytic Activity Suppresses Autoimmunity in a T Cell Intrinsic Manner.

MALT1 is a central signaling component in innate and adaptive immunity by regulating NF-κB and other key signaling pathways in different cell types. Activities of MALT1 are mediated by its scaffold and protease functions. Because of its role in lymphocyte activation and proliferation, inhibition of MALT1 proteolytic activity is of high interest for therapeutic targeting in autoimmunity and certain lymphomas.

Deletion of Mucosa-Associated Lymphoid Tissue Lymphoma Translocation Protein 1 in Mouse T Cells Protects Against Development of Autoimmune Arthritis but Leads to Spontaneous Osteoporosis.

Objective: Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT-1) plays a crucial role in innate and adaptive immune signaling by modulating the threshold for activation of immune cells, including Treg cells. Therefore, MALT-1 is regarded to be an interesting therapeutic target in several immune-mediated diseases. The goal of this study was to examine the role of MALT-1 in experimental animal models of rheumatoid arthritis (RA).

Targeting MALT1 Proteolytic Activity in Immunity, Inflammation and Disease: Good or Bad?

MALT1 is a signaling protein that plays a key role in immunity, inflammation, and lymphoid malignancies. For a long time MALT1 was believed to function as a scaffold protein, providing an assembly platform for other signaling proteins. This view changed dramatically when MALT1 was also found to have proteolytic activity and a capacity to fine-tune immune responses.

Pharmacological inhibition of MALT1 protease activity protects mice in a mouse model of multiple sclerosis.

Background: The paracaspase mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is crucial for lymphocyte activation through signaling to the transcription factor NF-κB. Besides functioning as a scaffold signaling protein, MALT1 also acts as a cysteine protease that specifically cleaves a number of substrates and contributes to specific T cell receptor-induced gene expression. Recently, small molecule inhibitors of MALT1 proteolytic activity were identified and shown to have promising anticancer properties in subtypes of B cell lymphoma.

T-cell receptor-induced JNK activation requires proteolytic inactivation of CYLD by MALT1.

The paracaspase mucosa-associated lymphoid tissue 1 (MALT1) is central to lymphocyte activation and lymphomagenesis. MALT1 mediates antigen receptor signalling to NF-κB by acting as a scaffold protein. Furthermore, MALT1 has proteolytic activity that contributes to optimal NF-κB activation by cleaving the NF-κB inhibitor A20.

Cleavage by MALT1 induces cytosolic release of A20.

The MALT1 paracaspase has arginine-directed proteolytic activity. A20 is a dual ubiquitin-editing enzyme involved in termination of NF-κB signaling. Upon T- or B-cell receptor engagement human (h) A20 is cleaved by MALT1 after arginine 439, yielding an N-terminal fragment (hA20p50) and a C-terminal one (hA20p37).