Brian Raught | UHN Research

Ubiquitin, a small and ancient signaling protein, is chemically attached to other proteins in the cell to mark them for destruction (in addition to other critical functions). Malfunctions in the ubiquitin system have been implicated in many disease states, including neurodegenerative disorders (e.g. Alzheimer's and Parkinson's diseases) and cancer.

The ubiquitin-like modifiers (ULMs) comprise a diverse group of small polypeptides (SUMO, ISG15, NEDD8/RUB1, URM1, FAT10, etc.) which, like ubiquitin, are also covalently conjugated to 'target' proteins (or other biomolecules) in a reversible manner. While these modifiers appear to play many critical roles in cell function, most of them remain very poorly understood.

Mass spectrometry (MS) has emerged as an extremely powerful tool to screen complex biological samples for many different types of post-translational modifications. Using a combination of MS and a novel software tool (SUMmOn), my colleagues and I developed the first automated approach for the identification of ULM target proteins and ULM attachment sites.

Using this technology, along with high throughput and quantitative proteomics approaches, my laboratory is focused on:
defining ubiquitin and ULM target protein populations in normal cells, and characterizing how these target populations differ between cell types, how they change throughout the cell cycle, and how they are altered in response to extracellular stress or stimuli. These data will help us to better define the cellular processes modulated by each of the different ULMs.

defining how ubiquitin and ULM target protein populations are altered in various disease states. This information will shed light on how ubiquitin and the ULMs are affected by, or contribute to, various types of pathologies.

characterizing how modification by ubiquitin or a ULM alters the activity of specific proteins involved in vital cellular processes. This will provide us with more specific knowledge regarding how a particular modification alters the function of an individual protein.

better understanding the amino acid sequence or structural elements that define the recognition sites for ubiquitin or ULM attachment. This information will help us to better understand and predict ubiquitin/ULM modification sites.

By shedding light on these critically important, yet poorly understood, signaling proteins, we hope to better understanding their roles in neurological diseases, cancer and viral infection.

Tyrosyl phosphorylation of KRAS stalls GTPase cycle via alteration of switch I and II conformation.

Nat Commun. 2019 Jan 15;10(1):224

Kano Y, Gebregiworgis T, Marshall CB, Radulovich N, Poon BPK, St-Germain J, Cook JD, Valencia-Sama I, Grant BMM, Herrera SG, Miao J, Raught B, Irwin MS, Lee JE, Yeh JJ, Zhang ZY, Tsao MS, Ikura M, Ohh M

An ATG16L1-dependent pathway promotes plasma membrane repair and limits Listeria monocytogenes cell-to-cell spread.

Nat Microbiol. 2018 Dec;3(12):1472-1485

Tan JMJ, Mellouk N, Osborne SE, Ammendolia DA, Dyer DN, Li R, Brunen D, van Rijn JM, Huang J, Czuczman MA, Cemma MA, Won AM, Yip CM, Xavier RJ, MacDuff DA, Reggiori F, Debnath J, Yoshimori T, Kim PK, Fairn GD, Coyaud E, Raught B, Muise AM, Higgins DE,...

Getting to know the neighborhood: using proximity-dependent biotinylation to characterize protein complexes and map organelles.

Curr Opin Chem Biol. 2018 Nov 17;48:44-54

Gingras AC, Abe KT, Raught B

MYC Protein Interactome Profiling Reveals Functionally Distinct Regions that Cooperate to Drive Tumorigenesis.

Mol Cell. 2018 Oct 30;:

Kalkat M, Resetca D, Lourenco C, Chan PK, Wei Y, Shiah YJ, Vitkin N, Tong Y, Sunnerhagen M, Done SJ, Boutros PC, Raught B, Penn LZ

MYC Interacts with the G9a Histone Methyltransferase to Drive Transcriptional Repression and Tumorigenesis.

Cancer Cell. 2018 Oct 08;34(4):579-595.e8

Tu WB, Shiah YJ, Lourenco C, Mullen PJ, Dingar D, Redel C, Tamachi A, Ba-Alawi W, Aman A, Al-Awar R, Cescon DW, Haibe-Kains B, Arrowsmith CH, Raught B, Boutros PC, Penn LZ

Ubiquitin ligase RNF8 suppresses Notch signaling to regulate mammary development and tumorigenesis.

J Clin Invest. 2018 Sep 17;:

Li L, Guturi KKN, Gautreau B, Patel PS, Saad A, Morii M, Mateo F, Palomero L, Barbour H, Gomez A, Ng D, Kotlyar M, Pastrello C, Jackson HW, Khokha R, Jurisica I, Affar EB, Raught B, Sanchez O, Alaoui-Jamali M, Pujana MA, Hakem A, Hakem R

PPP1R35 is a novel centrosomal protein that regulates centriole length in concert with the microcephaly protein RTTN.

Elife. 2018 Aug 31;7:

Sydor AM, Coyaud E, Rovelli C, Laurent E, Liu H, Raught B, Mennella V

MYC dephosphorylation by the PP1/PNUTS phosphatase complex regulates chromatin binding and protein stability.

Nat Commun. 2018 Aug 29;9(1):3502

Dingar D, Tu WB, Resetca D, Lourenco C, Tamachi A, De Melo J, Houlahan KE, Kalkat M, Chan PK, Boutros PC, Raught B, Penn LZ

Global interactomics uncovers extensive organellar targeting by Zika virus.

Mol Cell Proteomics. 2018 Jul 23;:

Coyaud E, Ranadheera C, Cheng DT, Goncalves J, Dyakov B, Laurent E, St-Germain JR, Pelletier L, Gingras AC, Brumell JH, Kim PK, Safronetz D, Raught B

Salmonella exploits host Rho GTPase signalling pathways through the phosphatase activity of SopB.

Cell Microbiol. 2018 Jul 16;:e12938

Truong D, Boddy KC, Canadien V, Brabant D, Fairn GD, D'Costa VM, Coyaud E, Raught B, Perez-Sala D, Park WS, Do Heo W, Grinstein S, Brumell JH