RhoG deficiency abrogates cytotoxicity of human lymphocytes and causes hemophagocytic lymphohistiocytosis.

Autor:	Kalinichenko A; St Anna Children's Cancer Research Institute (CCRI), Vienna, Austria.; Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria., Perinetti Casoni G; Center for Hematology and Regenerative Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden., Dupré L; Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria.; Toulouse Institute for Infectious and Inflammatory Diseases (INFINITy), INSERM, Centre National de la Recherche Scientifique (CNRS), Toulouse III Paul Sabatier University, Toulouse, France.; Department of Dermatology, Medical University of Vienna, Vienna, Austria., Trotta L; Institute for Molecular Medicine Finland, University of Helsinki, Finland., Huemer J; St Anna Children's Cancer Research Institute (CCRI), Vienna, Austria.; Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria., Galgano D; Center for Hematology and Regenerative Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden., German Y; Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria.; Toulouse Institute for Infectious and Inflammatory Diseases (INFINITy), INSERM, Centre National de la Recherche Scientifique (CNRS), Toulouse III Paul Sabatier University, Toulouse, France., Haladik B; St Anna Children's Cancer Research Institute (CCRI), Vienna, Austria.; Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria., Pazmandi J; St Anna Children's Cancer Research Institute (CCRI), Vienna, Austria.; Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria., Thian M; St Anna Children's Cancer Research Institute (CCRI), Vienna, Austria.; Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria., Yüce Petronczki Ö; St Anna Children's Cancer Research Institute (CCRI), Vienna, Austria.; Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria., Chiang SC; Center for Hematology and Regenerative Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden., Taskinen M; Rare Disease and Pediatric Research Centers, University of Helsinki and Helsinki University Hospital, Helsinki, Finland., Hekkala A; Oulu University Hospital and University of Oulu, Oulu, Finland., Kauppila S; Oulu University Hospital and University of Oulu, Oulu, Finland., Lindgren O; Oulu University Hospital and University of Oulu, Oulu, Finland., Tapiainen T; Oulu University Hospital and University of Oulu, Oulu, Finland., Kraakman MJ; St Anna Children's Cancer Research Institute (CCRI), Vienna, Austria.; Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria., Vettenranta K; Rare Disease and Pediatric Research Centers, University of Helsinki and Helsinki University Hospital, Helsinki, Finland., Lomakin AJ; St Anna Children's Cancer Research Institute (CCRI), Vienna, Austria.; Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria., Saarela J; Institute for Molecular Medicine Finland, University of Helsinki, Finland.; Department of Clinical Genetics, Helsinki University Hospital, Helsinki, Finland.; Centre for Molecular Medicine Norway, University of Oslo, Norway., Seppänen MRJ; Rare Disease and Pediatric Research Centers, University of Helsinki and Helsinki University Hospital, Helsinki, Finland., Bryceson YT; Center for Hematology and Regenerative Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.; Broegelmann Research Laboratory, Department of Clinical Sciences, University of Bergen, Bergen, Norway., Boztug K; St Anna Children's Cancer Research Institute (CCRI), Vienna, Austria.; Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria.; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.; Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria; and.; St Anna Children's Hospital, Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.
Jazyk:	angličtina
Zdroj:	Blood [Blood] 2021 Apr 15; Vol. 137 (15), pp. 2033-2045.
DOI:	10.1182/blood.2020008738
Abstrakt:	Exocytosis of cytotoxic granules (CG) by lymphocytes is required for the elimination of infected and malignant cells. Impairments in this process underly a group of diseases with dramatic hyperferritinemic inflammation termed hemophagocytic lymphohistiocytosis (HLH). Although genetic and functional studies of HLH have identified proteins controlling distinct steps of CG exocytosis, the molecular mechanisms that spatiotemporally coordinate CG release remain partially elusive. We studied a patient exhibiting characteristic clinical features of HLH associated with markedly impaired cytotoxic T lymphocyte (CTL) and natural killer (NK) cell exocytosis functions, who beared biallelic deleterious mutations in the gene encoding the small GTPase RhoG. Experimental ablation of RHOG in a model cell line and primary CTLs from healthy individuals uncovered a hitherto unappreciated role of RhoG in retaining CGs in the vicinity of the plasma membrane (PM), a fundamental prerequisite for CG exocytotic release. We discovered that RhoG engages in a protein-protein interaction with Munc13-4, an exocytosis protein essential for CG fusion with the PM. We show that this interaction is critical for docking of Munc13-4+ CGs to the PM and subsequent membrane fusion and release of CG content. Thus, our study illuminates RhoG as a novel essential regulator of human lymphocyte cytotoxicity and provides the molecular pathomechanism behind the identified here and previously unreported genetically determined form of HLH. (© 2021 by The American Society of Hematology.)
Databáze:	MEDLINE
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