title: A role for MALT1 activity in Kaposi's sarcoma-associated herpes virus latency and growth of primary effusion lymphoma.
abstract: Primary effusion lymphoma (PEL) is an incurable malignancy that develops in immunodeficient patients as a consequence of latent infection of B-cells with Kaposi's sarcoma-associated herpes virus (KSHV). Malignant growth of KSHV-infected B cells requires the activity of the transcription factor nuclear factor (NF)-κB, which controls maintenance of viral latency and suppression of the viral lytic program. Here we show that the KSHV proteins K13 and K15 promote NF-κB activation via the protease mucosa-associated lymphoid tissue lymphoma translocation protein-1 (MALT1), a key driver of NF-κB activation in lymphocytes. Inhibition of the MALT1 protease activity induced a switch from the latent to the lytic stage of viral infection, and led to reduced growth and survival of PEL cell lines in vitro and in a xenograft model. These results demonstrate a key role for the proteolytic activity of MALT1 in PEL, and provide a rationale for the pharmacological targeting of MALT1 in PEL therapy.
authors.affiliation: Department of Biochemistry, Center of Immunity and Infection, University of Lausanne, Epalinges, Switzerland.
authors.forename: L
authors.initials: L
authors.lastname: Bonsignore
authors.affiliation: Department of Biochemistry, Center of Immunity and Infection, University of Lausanne, Epalinges, Switzerland.
authors.forename: K
authors.initials: K
authors.lastname: Passelli
authors.affiliation: Department of Biochemistry, Center of Immunity and Infection, University of Lausanne, Epalinges, Switzerland.
authors.forename: C
authors.initials: C
authors.lastname: Pelzer
authors.affiliation: Department of Biochemistry, Center of Immunity and Infection, University of Lausanne, Epalinges, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Perroud
authors.affiliation: Division of Molecular and Experimental Surgery, University Medical Center Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Translational Research Center, CIIL Biomedical Research Center, Erlangen, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Konrad
authors.affiliation: Division of Molecular and Experimental Surgery, University Medical Center Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Translational Research Center, CIIL Biomedical Research Center, Erlangen, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Thurau
authors.affiliation: Division of Molecular and Experimental Surgery, University Medical Center Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Translational Research Center, CIIL Biomedical Research Center, Erlangen, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Stürzl
authors.affiliation: Department of Microbiology, Immunology & Parasitology, Louisiana State University Health Sciences Center, Louisiana Cancer Research Center, New Orleans, LA, USA.|Department of Oncology, Research Center for Translational Medicine and Key Laboratory of Arrhythmias, East Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: L
authors.initials: L
authors.lastname: Dai
authors.affiliation: Department of Pathology, Louisiana State University Health Sciences Center, Louisiana State University Health Sciences Center, Louisiana Cancer Research Center, New Orleans, LA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Trillo-Tinoco
authors.affiliation: Department of Pathology, Louisiana State University Health Sciences Center, Louisiana State University Health Sciences Center, Louisiana Cancer Research Center, New Orleans, LA, USA.
authors.forename: L
authors.initials: L
authors.lastname: Del Valle
authors.affiliation: Department of Microbiology, Immunology & Parasitology, Louisiana State University Health Sciences Center, Louisiana Cancer Research Center, New Orleans, LA, USA.|Department of Oncology, Research Center for Translational Medicine and Key Laboratory of Arrhythmias, East Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Qin
authors.affiliation: Department of Biochemistry, Center of Immunity and Infection, University of Lausanne, Epalinges, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Thome
mesh_terms: D000818:Animals; D015415:Biomarkers; D020169:Caspases / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002470:Cell Survival / Q000235:genetics; D004195:Disease Models, Animal; D004789:Enzyme Activation; D005434:Flow Cytometry; D020868:Gene Silencing; D006566:Herpesviridae Infections / Q000150:complications* / Q000821:virology*; D019288:Herpesvirus 8, Human / Q000502:physiology*; D054884:Host-Pathogen Interactions; D006801:Humans; D054685:Lymphoma, Primary Effusion / Q000209:etiology* / Q000473:pathology*; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; D016328:NF-kappa B / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D014764:Viral Proteins / Q000378:metabolism; D014775:Virus Activation; D017735:Virus Latency; D023041:Xenograft Model Antitumor Assays
chemical_list: D015415:Biomarkers; D016328:NF-kappa B; D009363:Neoplasm Proteins; D014764:Viral Proteins; D020169:Caspases; C400109:MALT1 protein, human; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein