Regulation of endosomal sorting
Early work on pro-inflammatory gene transcription (see below) led us to the discovery of the COMMD protein family, which is defined by a unique domain (a). Nearly at the same time as our work implicated COMMD1 in immune regulation, genetic studies identified this factor as playing a central role in copper metabolism, through unclear mechanisms. We discovered that COMMD1 regulates cellular copper through a previously unknown protein complex that controls recycling of proteins from the endosomal compartment – we identified and reported the existence of this molecular assembly known as the CCC protein complex (b). Thereafter, we identified that CCC regulates a novel cargo recognition complexed that we named Retriever (c) and most recently we described that CCC works through the regulation of endosomal levels of phosphoinositide-3-phoshate (d).
We are currently investigating how these steps regulate nutrient homeostasis through trafficking of key surface transporters and how these events are controlled by lipid phosphatases associated to the CCC complex (R01 DK107733).
- Burstein E, Hoberg JE, Wilkinson AS, Rumble JM, Csomos RA, Komarck CM, Maine GN, Wilkinson JC, Mayo MW, Duckett CS. COMMD Proteins: a novel family of structural and functional homologs of MURR1.Journal of Biological Chemistry, 280: 22222-22232 (2005). PMID: 15799966.
- Phillips-Krawczak CA‡, Singla A‡, Starokadomskyy P, Deng Z, Osborne DG, Li H, Dick CJ, Gomez TS, Koenecke M, Zhang J-S, Dai H, Kaufmann SH, Hein MY, Wallis M, McGaughran J, Gecz J, van de Sluis B, Billadeau DD, Burstein E. COMMD1 is linked to the WASH complex and regulates endosomal trafficking of the copper transporter ATP7A. Molecular Biology of the Cell,26: 91-103 (2015). PMC4279232.
- McNally KE, Faulkner R, Steinberg F, Gallon M, Ghai R, Pim D, Langton P, Pearson N, Danson CM, Nägele H, Morris LM, Singla A, Overlee BL, Heesom KJ, Sessions R, Banks L, Collins BM, Berger I, Billadeau DD, Burstein E, Cullen PJ. Retriever, a multiprotein complex for retromer-independent endosomal cargo recycling. Nature Cell Biology, 19: 1214-1225(2017). PMC5790113.
- Singla A, Fedoseienko A, Giridharan SSP, Overlee BL, Lopez A, Jia D, Song J, Huff-Hardy K, Weisman L, Burstein E, Billadeau DD. Endosomal PI(3)P regulation by the CCC complex controls membrane protein recycling. Co-corresponding authors. Nature Communications, 10: 4271 (2019).