Makoto Nakashima1,2, Mariko Watanabe1,3, Kaoru Uchimaru2, Ryouichi Horie1,3. 1. Department of Molecular Hematology, Faculty of Molecular Medical Biology, Graduate School of Medical Sciences, Kitasato University, Minami-ku, Sagamihara, Kanagawa, 252-0374, Japan. 2. Laboratory of Tumor Cell Biology, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, University of Tokyo, Minato-ku, Tokyo, 108-8639, Japan. 3. Division of Hematology, Department of Laboratory Sciences, School of Allied Health Sciences, Kitasato University, Minami-ku, Sagamihara, Kanagawa, 252-0373, Japan.
Abstract
BACKGROUND INFORMATION: CD30, which is characteristically expressed in classical Hodgkin lymphoma (cHL), is thought to transduce signals by ligation of trimerised CD30 ligand (CD30L) on the surface of surrounding cells and recruitment of downstream molecules. In this report, we propose a new mechanism for CD30 signalling by its ligand. We prepared two stable transformants, CHO cells expressing CD30L fused to mCherry and HeLa cells expressing CD30 fused to GFP. RESULTS: Co-culture of these cells triggered clustering of CD30 and CD30L at the cellular interface, formation of multiple CD30L-CD30 complexes, internalisation of these complexes with a portion of the plasma membrane into the HeLa cells, and intracellular transport to the lysosomal compartment. The internalisation process was significantly inhibited by actin polymerisation inhibitors. The CD30L-CD30 interaction was found to trigger active signalling processes, as measured by Ca2+ influx, and similar mechanisms were observed using cHL cell lines. CONCLUSIONS: These results suggest that CD30 extracts CD30L from CD30L-expressing cells by actin-mediated trogocytosis, resulting in the generation of signalosomes, intracellular signalling, lysosomal degradation and a subsequent refractory phase. We postulate that similar processes may operate in tumours endogenously expressing CD30. These observations thus provide new insights into our understanding of the biological roles of CD30 in normal and malignant cells and, in particular, in cHL. SIGNIFICANCE: This study suggests a novel model of CD30 signalling that provides new insights into the biological roles of CD30 and other members of this family in normal and malignant cells.
BACKGROUND INFORMATION: CD30, which is characteristically expressed in classical Hodgkin lymphoma (cHL), is thought to transduce signals by ligation of trimerised CD30 ligand (CD30L) on the surface of surrounding cells and recruitment of downstream molecules. In this report, we propose a new mechanism for CD30 signalling by its ligand. We prepared two stable transformants, CHO cells expressing CD30L fused to mCherry and HeLa cells expressing CD30 fused to GFP. RESULTS: Co-culture of these cells triggered clustering of CD30 and CD30L at the cellular interface, formation of multiple CD30L-CD30 complexes, internalisation of these complexes with a portion of the plasma membrane into the HeLa cells, and intracellular transport to the lysosomal compartment. The internalisation process was significantly inhibited by actin polymerisation inhibitors. The CD30L-CD30 interaction was found to trigger active signalling processes, as measured by Ca2+ influx, and similar mechanisms were observed using cHL cell lines. CONCLUSIONS: These results suggest that CD30 extracts CD30L from CD30L-expressing cells by actin-mediated trogocytosis, resulting in the generation of signalosomes, intracellular signalling, lysosomal degradation and a subsequent refractory phase. We postulate that similar processes may operate in tumours endogenously expressing CD30. These observations thus provide new insights into our understanding of the biological roles of CD30 in normal and malignant cells and, in particular, in cHL. SIGNIFICANCE: This study suggests a novel model of CD30 signalling that provides new insights into the biological roles of CD30 and other members of this family in normal and malignant cells.
Authors: Sakthi Rajendran; Yating Li; Evelyn Ngoh; Hiu Yi Wong; Man Si Cheng; Cheng-I Wang; Herbert Schwarz Journal: Front Oncol Date: 2019-09-24 Impact factor: 6.244
Authors: Mohamed S Hasim; Marie Marotel; Jonathan J Hodgins; Elisabetta Vulpis; Olivia J Makinson; Sara Asif; Han-Yun Shih; Amit K Scheer; Olivia MacMillan; Felipe G Alonso; Kelly P Burke; David P Cook; Rui Li; Maria Teresa Petrucci; Angela Santoni; Padraic G Fallon; Arlene H Sharpe; Giuseppe Sciumè; André Veillette; Alessandra Zingoni; Douglas A Gray; Arleigh McCurdy; Michele Ardolino Journal: Sci Adv Date: 2022-04-13 Impact factor: 14.957