The transmembrane domains of TNF-related apoptosis-inducing ligand (TRAIL) receptors 1 and 2 co-regulate apoptotic signaling capacity.
TNF-related apoptosis-inducing ligand (TRAIL) is a member of the tumor necrosis factor (TNF) ligand family that exerts its apoptotic activity in human cells by binding to two transmembrane receptors, TRAILR1 and TRAILR2. In cells co-expressing both receptors the particular contribution of either pro...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2012-01-01
|
| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3420232?pdf=render |
| _version_ | 1819042258408701952 |
|---|---|
| author | Simon Neumann Tobias Bidon Marcus Branschädel Anja Krippner-Heidenreich Peter Scheurich Malgorzata Doszczak |
| author_facet | Simon Neumann Tobias Bidon Marcus Branschädel Anja Krippner-Heidenreich Peter Scheurich Malgorzata Doszczak |
| author_sort | Simon Neumann |
| collection | DOAJ |
| description | TNF-related apoptosis-inducing ligand (TRAIL) is a member of the tumor necrosis factor (TNF) ligand family that exerts its apoptotic activity in human cells by binding to two transmembrane receptors, TRAILR1 and TRAILR2. In cells co-expressing both receptors the particular contribution of either protein to the overall cellular response is not well defined. Here we have investigated whether differences in the signaling capacities of TRAILR1 and TRAILR2 can be attributed to certain functional molecular subdomains. We generated and characterized various chimeric receptors comprising TRAIL receptor domains fused with parts from other members of the TNF death receptor family. This allowed us to compare the contribution of particular domains of the two TRAIL receptors to the overall apoptotic response and to identify elements that regulate apoptotic signaling. Our results show that the TRAIL receptor death domains are weak apoptosis inducers compared to those of CD95/Fas, because TRAILR-derived constructs containing the CD95/Fas death domain possessed strongly enhanced apoptotic capabilities. Importantly, major differences in the signaling strengths of the two TRAIL receptors were linked to their transmembrane domains in combination with the adjacent extracellular stalk regions. This was evident from receptor chimeras comprising the extracellular part of TNFR1 and the intracellular signaling part of CD95/Fas. Both receptor chimeras showed comparable ligand binding affinities and internalization kinetics. However, the respective TRAILR2-derived molecule more efficiently induced apoptosis. It also activated caspase-8 and caspase-3 more strongly and more quickly, albeit being expressed at lower levels. These results suggest that the transmembrane domains together with their adjacent stalk regions can play a major role in control of death receptor activation thereby contributing to cell type specific differences in TRAILR1 and TRAILR2 signaling. |
| first_indexed | 2024-12-21T09:38:02Z |
| format | Article |
| id | doaj.art-b4efd875d417403ab0654027ab7a4e69 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-21T09:38:02Z |
| publishDate | 2012-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-b4efd875d417403ab0654027ab7a4e692022-12-21T19:08:34ZengPublic Library of Science (PLoS)PLoS ONE1932-62032012-01-0178e4252610.1371/journal.pone.0042526The transmembrane domains of TNF-related apoptosis-inducing ligand (TRAIL) receptors 1 and 2 co-regulate apoptotic signaling capacity.Simon NeumannTobias BidonMarcus BranschädelAnja Krippner-HeidenreichPeter ScheurichMalgorzata DoszczakTNF-related apoptosis-inducing ligand (TRAIL) is a member of the tumor necrosis factor (TNF) ligand family that exerts its apoptotic activity in human cells by binding to two transmembrane receptors, TRAILR1 and TRAILR2. In cells co-expressing both receptors the particular contribution of either protein to the overall cellular response is not well defined. Here we have investigated whether differences in the signaling capacities of TRAILR1 and TRAILR2 can be attributed to certain functional molecular subdomains. We generated and characterized various chimeric receptors comprising TRAIL receptor domains fused with parts from other members of the TNF death receptor family. This allowed us to compare the contribution of particular domains of the two TRAIL receptors to the overall apoptotic response and to identify elements that regulate apoptotic signaling. Our results show that the TRAIL receptor death domains are weak apoptosis inducers compared to those of CD95/Fas, because TRAILR-derived constructs containing the CD95/Fas death domain possessed strongly enhanced apoptotic capabilities. Importantly, major differences in the signaling strengths of the two TRAIL receptors were linked to their transmembrane domains in combination with the adjacent extracellular stalk regions. This was evident from receptor chimeras comprising the extracellular part of TNFR1 and the intracellular signaling part of CD95/Fas. Both receptor chimeras showed comparable ligand binding affinities and internalization kinetics. However, the respective TRAILR2-derived molecule more efficiently induced apoptosis. It also activated caspase-8 and caspase-3 more strongly and more quickly, albeit being expressed at lower levels. These results suggest that the transmembrane domains together with their adjacent stalk regions can play a major role in control of death receptor activation thereby contributing to cell type specific differences in TRAILR1 and TRAILR2 signaling.http://europepmc.org/articles/PMC3420232?pdf=render |
| spellingShingle | Simon Neumann Tobias Bidon Marcus Branschädel Anja Krippner-Heidenreich Peter Scheurich Malgorzata Doszczak The transmembrane domains of TNF-related apoptosis-inducing ligand (TRAIL) receptors 1 and 2 co-regulate apoptotic signaling capacity. PLoS ONE |
| title | The transmembrane domains of TNF-related apoptosis-inducing ligand (TRAIL) receptors 1 and 2 co-regulate apoptotic signaling capacity. |
| title_full | The transmembrane domains of TNF-related apoptosis-inducing ligand (TRAIL) receptors 1 and 2 co-regulate apoptotic signaling capacity. |
| title_fullStr | The transmembrane domains of TNF-related apoptosis-inducing ligand (TRAIL) receptors 1 and 2 co-regulate apoptotic signaling capacity. |
| title_full_unstemmed | The transmembrane domains of TNF-related apoptosis-inducing ligand (TRAIL) receptors 1 and 2 co-regulate apoptotic signaling capacity. |
| title_short | The transmembrane domains of TNF-related apoptosis-inducing ligand (TRAIL) receptors 1 and 2 co-regulate apoptotic signaling capacity. |
| title_sort | transmembrane domains of tnf related apoptosis inducing ligand trail receptors 1 and 2 co regulate apoptotic signaling capacity |
| url | http://europepmc.org/articles/PMC3420232?pdf=render |
| work_keys_str_mv | AT simonneumann thetransmembranedomainsoftnfrelatedapoptosisinducingligandtrailreceptors1and2coregulateapoptoticsignalingcapacity AT tobiasbidon thetransmembranedomainsoftnfrelatedapoptosisinducingligandtrailreceptors1and2coregulateapoptoticsignalingcapacity AT marcusbranschadel thetransmembranedomainsoftnfrelatedapoptosisinducingligandtrailreceptors1and2coregulateapoptoticsignalingcapacity AT anjakrippnerheidenreich thetransmembranedomainsoftnfrelatedapoptosisinducingligandtrailreceptors1and2coregulateapoptoticsignalingcapacity AT peterscheurich thetransmembranedomainsoftnfrelatedapoptosisinducingligandtrailreceptors1and2coregulateapoptoticsignalingcapacity AT malgorzatadoszczak thetransmembranedomainsoftnfrelatedapoptosisinducingligandtrailreceptors1and2coregulateapoptoticsignalingcapacity AT simonneumann transmembranedomainsoftnfrelatedapoptosisinducingligandtrailreceptors1and2coregulateapoptoticsignalingcapacity AT tobiasbidon transmembranedomainsoftnfrelatedapoptosisinducingligandtrailreceptors1and2coregulateapoptoticsignalingcapacity AT marcusbranschadel transmembranedomainsoftnfrelatedapoptosisinducingligandtrailreceptors1and2coregulateapoptoticsignalingcapacity AT anjakrippnerheidenreich transmembranedomainsoftnfrelatedapoptosisinducingligandtrailreceptors1and2coregulateapoptoticsignalingcapacity AT peterscheurich transmembranedomainsoftnfrelatedapoptosisinducingligandtrailreceptors1and2coregulateapoptoticsignalingcapacity AT malgorzatadoszczak transmembranedomainsoftnfrelatedapoptosisinducingligandtrailreceptors1and2coregulateapoptoticsignalingcapacity |