title: CC2D1A and CC2D1B regulate degradation and signaling of EGFR and TLR4.
abstract: Signaling through many transmembrane receptors is terminated by their sorting to the intraluminal vesicles (ILVs) of multivescular bodies (MVBs) and subsequent lysosomal degradation. ILV formation requires the endosomal sorting complex required for transport (ESCRT) machinery. CC2D1A and CC2D1B interact with the CHMP4 family of proteins, the major subunit of the ESCRT-III complex, however, their roles in receptor degradation and signaling are poorly defined. Here, we report that CC2D1A binds to CHMP4B polymers formed on endosomes to regulate the endosomal sorting pathway. We show that depletion of CC2D1A and B accelerates degradation of EGFR and elicits rapid termination of its downstream signaling through ERK1 and 2. Depletion of CC2D1A and B promotes sorting of EGFR to ILV leading to its rapid lysosomal degradation. In addition, we show that knockdown of CC2D1A and B has similar effects on degradation and downstream signaling of another membrane receptor, TLR4. Thus, these findings suggest that CC2D1A and B may have broad effects on transmembrane receptors by preventing premature ILV sorting and termination of signaling.
authors: Department of Medical Lifesciences, The Catholic University of Korea, Seoul 137-701, South Korea.
authors: Rakesh
authors: R
authors: Deshar
authors: Department of Biochemistry and Translational Research Center for Protein Function Control, Yonsei University, Seoul 120-749, South Korea.
authors: Eun-Bee
authors: EB
authors: Cho
authors: Department of Medical Lifesciences, The Catholic University of Korea, Seoul 137-701, South Korea. Electronic address: sjkyoon@catholic.ac.kr.
authors: Sungjoo Kim
authors: SK
authors: Yoon
authors: Department of Biochemistry and Translational Research Center for Protein Function Control, Yonsei University, Seoul 120-749, South Korea. Electronic address: yoonj@yonsei.ac.kr.
authors: Jong-Bok
authors: JB
authors: Yoon
mesh_terms: D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D056827:Endosomal Sorting Complexes Required for Transport / Q000378:metabolism; D011992:Endosomes / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D021381:Protein Transport; D059748:Proteolysis; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
chemical_list: C512283:CC2D1A protein, human; C544137:CC2D1B protein, human; C478397:CHMP4B protein, human; D004268:DNA-Binding Proteins; D056827:Endosomal Sorting Complexes Required for Transport; D012097:Repressor Proteins; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; C512478:EGFR protein, human; D066246:ErbB Receptors
keywords: CC2D1A; CHMP4B; ESCRT; Endosome; Membrane receptor complex