Membrane Traffic
Colin Adrain
One third of proteins encoded by eukaryotic genomes undergo their biogenesis in an essential membranous organelle called the endoplasmic reticulum (ER)—the cell’s protein factory. Many of these proteins are integral membrane proteins, which must fold in the ER and be inserted into the ER membrane. Following their successful membrane import, these proteins are trafficked through a network of membranous organelles called the secretory pathway.
When membrane proteins are trafficked to their final destination (e.g. the plasma membrane) they fulfill multiple important physiological roles essential for eukaryotic life, including cell signaling.
Surprisingly, the complex biogenesis of many signaling proteins, including those associated with human diseases, remains poorly understood. This, combined with the fact that approximately 60% of current drugs target membrane proteins, illustrates the importance to understand how membrane proteins are successfully made, integrated into the membrane and trafficked within the secretory pathway.
The Membrane Traffic lab is interested in several aspects of membrane protein homeostasis (‘Proteostasis’) including how membrane proteins are made, degraded or trafficked within the secretory pathway.
We use a combination of cellular biochemistry and mouse physiology in our experimental approaches, focusing particularly on models of inflammation and/or metabolic homeostasis.
Our work currently focuses on three areas being developed:
- How membrane trafficking regulates signalling controlled by the metalloprotease ADAM17/TACE.
- Role of quality control in the secretory pathway in vivo in mice, during development and disease.
- Genetic screens to identify novel trafficking factors.
Projects
Among the critical players in defining membrane identity and function are Rab GTPases. More than 60 Rabs have been identified in mammalian cells and each one exhibits a specific subcellular localisation. Upon activation by binding GTP, Rabs recruit effector proteins such as molecular motors, enzymes (e.g. PI-3 kinase) and membrane fusion factors, thus conferring specific functions to their target organelles. We are interested in membrane traffic and in particular in the role of Rab GTPases and their interacting partners in the control of vesicle trafficking and organelle motility.
These processes are relevant to many diseases, genetic and acquired. Our approach is to combine fundamental and pathogenesis studies as we believe that each aspect reinforces the other. Therefore, we work on cellular pathogenetic processes that involve dysfunction of intracellular membrane traffic pathways as follows:
1) Host/pathogen interactions in malaria
2) Membrane traffic, retinal pigment epithelium and retinal degenera-tion
3) Novel Therapies
4) Rabs and membrane traffic
5) Molecular Basis of Membrane Identity: Lipid Modifications of Rab GTPases and Membrane Targeting
For more information on each project please click here (PDF)
Publications
- Gaspar, Catarina J ; Vieira, Lígia C; Santos, Cristiana C ; Christianson, John C; Jakubec, David ; Strisovsky, Kvido; Adrain, Colin and Domingos, Pedro M. (2021) EMC is required for biogenesis of Xport-A, an essential chaperone of Rhodopsin-1 and the TRP channel. EMBO Reports e53210
- Badenes, Marina; Amin, Abdulbasit; González-García, Ismael; Félix, Inês; Burbridge, Emma; Cavadas, Miguel; Ortega, Francisco José; de Carvalho, Érika; Faísca, Pedro; Carobbio, Stefania; Seixas, Elsa; Pedroso, Dora; Neves-Costa, Ana; Moita, Luís F.; Fernández-Real, José Manuel; Vidal-Puig, António; Domingos, Ana; López, Miguel; Adrain, Colin (2020) Deletion of iRhom2 protects against diet-induced obesity by increasing thermogenesis. Molecular Metabolism 31:67-84
- Marina Badenes and Colin Adrain (2019) iRhom2 and TNF: Partners or enemies?. Science Signaling 12
- Ioanna Oikonomidi, Emma Burbridge, Miguel Cavadas, Graeme Sullivan, Blanka Collis, Heike Naegele, Danielle Clancy, Jana Brezinova, Tianyi Hu, Andrea Bileck, Christopher Gerner, Alfonso Bolado, Alex von Kriegsheim, Seamus J Martin, Florian Steinberg, Kvido Strisovsky, Colin Adrain (2018) iTAP, a novel iRhom interactor, controls TNF secretion by policing the stability of iRhom/TACE. eLife 7:e35032
- Cavadas, M., Oikonomidi, I., Gaspar, C.J., Burbridge, E., Badenes, M., Félix, I., Bolado, A., Hu, T., Bileck, A., Gerner, C., Domingos, P.M., von Kreigsheim, A., Adrain C. (2017) Phosphorylation of iRhom2 Controls Stimulated Proteolytic Shedding by the Metalloprotease ADAM17/TACE.. Cell Rep. 21:745–757
- Miguel Cavadas , Ioanna Oikonomidi , Catarina J Gaspar , Emma Burbridge , Marina Badenes, Inês Félix , Alfonso Bolado , Tianyi Hu , Andrea Bileck , Christopher Gerner , Pedro M Domingos , Alex von Kriegsheim , Colin Adrain (2017) Phosphorylation of iRhom2 Controls Stimulated Proteolytic Shedding by the Metalloprotease ADAM17/TACE. Cell Rep. 21(3):745-757
- Johnson, N., Březinová, J., Stephens, E., Burbridge, E., Freeman, M., Adrain, C*., Strisovsky*, K. (2017) Quantitative proteomics screen identifies a substrate repertoire of rhomboid protease RHBDL2 in human cells and implicates it in epithelial homeostasis.. Sci Rep. 7:4277
- Adrain, C., Zettl, M., Christova, Y., Taylor, N., Freeman, M. (2012) Tumor necrosis factor signaling requires iRhom2 to promote trafficking and activation of TACE . (joint-first author).. Science 355:225-8
- Adrain, C., Strisovsky, K., Zettl, M., Hu, L., Lemberg, M.K., Freeman, M. (2011) Mammalian EGF receptor activation by the rhomboid protease RHBDL2.. EMBO Rep. 12:421-7
- Zettl, M., Adrain, C. , Strisovsky, K., Lastun, V., Freeman, M. (2011) Rhomboid family pseudoproteases use the ER quality control machinery to regulate intercellular signaling.. Cell 145:79-91
- Adrain, C. , Duriez, P.J., Brumatti, G., Delivani, P., Martin, S.J. (2006) The cytotoxic lymphocyte protease, granzyme B, targets the cytoskeleton and perturbs microtubule polymerization dynamics. J Biol Chem 281:8118-25
- Delivani, P., Adrain, C. , Taylor, R.C., Duriez, P.J., Martin, S.J. (2006) Role for CED-9 and Egl-1 as regulators of mitochondrial fission and fusion dynamics. Mol Cell 21:761-73
- Adrain, C. , Murphy, B.M., Martin, S.J. (2005) Molecular ordering of the caspase activation cascade initiated by the CTL/NK protease, Granzyme B. J. Biol. Chem 280:4663-4673
- Adrain, C. , Creagh, E.M., Cullen, S.P., Martin, S.J. (2004) Caspase-dependent inactivation of proteasome function during programmed cell death in Drosophila and man (joint-first author). J. Biol. Chem 279:36923-36930
- Adrain, C., Creagh, E.M., Martin, S.J. (2001) Apoptosis-associated release of Smac/DIABLO from mitochondria requires active caspases and is blocked by Bcl-2.. EMBO J. 20:6627-36
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