Our team studies the complex mechanisms that control the specific and regulated degradation of intracellular proteins. This process, called intracellular proteolysis, is essential because it is directly involved in the control of the protein expression level and timing that must be adjusted precisely and individually to the cell needs.
Intracellular proteolysis has multiple roles, and its dysfunctions are involved in many disorders, including cancer and neuro-degenerative diseases, such as Alzheimer’s or Parkinson’s disease. It is, therefore, very important to understand the biological roles and the mechanisms of action of the systems responsible for intracellular proteolysis.
In this context, our research team studies the ubiquitin-proteasome system. This pathway involves highly sophisticated mechanisms that mobilize, in total, hundreds of components to specifically recognize protein substrates.
At the heart of this system are the Proteasomes, molecular machines that hydrolyse proteins into biologically inactive peptides.
Proteasomes form a family of protein complexes that share a common proteolytic core (the 20S proteasome). However, the regulatory complexes that associate with this core are different and this feature is important in particular for substrate selection.
In our team, we study primarily the regulation, biological functions and mechanisms of action of PA28, one of these proteasome regulators. PA28γ is involved in the control of the cell nucleus architecture and in the stress response, and seems to play a key role in the development of certain cancers.
We presently follow two main research axes on PA28γ.
The aim of the first axis is to understand the biological roles of a major interactor of PA28γ that we have identified and called PIP30. PIP30 is a dimeric protein that binds to PA28γ and regulates its functions. We have recently demonstrated that PIP30 is involved in the regulation of nuclear structures called “Cajal bodies”, by modulating the association of PA28γ with components of these bodies.
The second research axis concerns the study of a novel role of PA28γ in chromatin control. Chromatin is made of DNA and proteins that regulate directly its organization and gene expression. Chromatin is an extremely organized, but also very dynamic structure. We discovered that PA28γ plays an important role in chromatin organization, and we are currently dissecting the involved mechanisms.
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Members of the team
(Staff Scientist) +33 (0)4 34 35 95 43
(Staff Scientist) +33 (0)4 34 35 95 42
(Staff Scientist) +33 (0)4 34 35 95 42
(Staff Scientist) +33 (0)4 34 35 95 53
The HslV Protease from Leishmania major and Its Activation by C-terminal HslU Peptides.
Kebe NM, Samanta K, Singh P, Lai-Kee-Him J, Apicella V, Payrot N, Lauraire N, Legrand B, Lisowski V, Mbang-Benet D,[...]
Int J Mol Sci. 20(5). Pubmed
Proteasome 19S RP and translation preinitiation complexes are secreted within exosomes upon serum starvation.
Bec N, Bonhoure A, Henry L, Berry L, Larroque C, Coux O, Stoebner PE, Vidal M.
Traffic. (7):516-536. Pubmed
PROTEOSTASIS: A European Network to Break Barriers and Integrate Science on Protein Homeostasis.
Dissmeyer N, Coux O, Rodriguez MS, Barrio R; Core Group Members of PROTEOSTASIS.
Trends Biochem Sci. pii: S0968-0004(19)30007-6. Pubmed
PIP30/FAM192A is a novel regulator of the nuclear proteasome activator PA28γ.
Jonik-Nowak B, Menneteau T, Fesquet D, Baldin V, Bonne-Andrea C, Méchali F, Fabre B, Boisguerin P, de Rossi S, Henriquet[...]
Proc Natl Acad Sci U S A. pii: 201722299. Pubmed
The stability of Fbw7α in M-phase requires its phosphorylation by PKC.
Zitouni S, Méchali F, Papin C, Choquet A, Roche D, Baldin V, Coux O, Bonne-Andrea C.
PLoS One. 12(8):e0183500. Pubmed
The proteasome maturation protein POMP increases proteasome assembly and activity in psoriatic lesional skin.
Zieba BA, Henry L, Lacroix M, Jemaà M, Lavabre-Bertrand T, Meunier L, Coux O, Stoebner PE.
J Dermatol Sci. S0923-1811(16)31057-X Pubmed
Inhibition of Proteasome Activity Induces Formation of Alternative Proteasome Complexes.
Welk V, Coux O, Kleene V, Abeza C, Trümbach D, Eickelberg O, Meiners S.
J Biol Chem. 291:13147-59. Pubmed
Extracting, enriching, and identifying nuclear body sub-complexes using label-based quantitative mass spectrometry.
Fox A, Mehta V, Boulon S, Trinkle-Mulcahy L.
Methods Mol Biol. 1262:215-38. Pubmed
Evolution of proteasome regulators in eukaryotes.
Fort P, Kajava AV, Delsuc F, Coux O.
Genome Biol Evol. 7:1363-79. Pubmed
Kizuna is a novel mitotic substrate for CDC25B phosphatase.
Thomas Y, Peter M, Mechali F, Blanchard JM, Coux O, Baldin V.
Cell Cycle. 13:3867-77. Pubmed
The bacterial-like HslVU protease complex subunits are involved in the control of different cell cycle events in trypanosomatids.
Mbang-Benet DE, Sterkers Y, Morelle C, Kebe NM, Crobu L, Portalès P, Coux O, Hernandez JF, Meghamla S, Pagès M,[...]
Acta Trop. 131:22-31. Pubmed
High-resolution live-cell imaging reveals novel cyclin A2 degradation foci involving autophagy.
Loukil A, Zonca M, Rebouissou C, Baldin V, Coux O, Biard-Piechaczyk M, Blanchard JM, Peter M.
J Cell Sci. 127:2145-50. Pubmed
Proteomic and 3D structure analyses highlight the C/D box snoRNP assembly mechanism and its control.
Bizarro J, Charron C, Boulon S, Westman B, Pradet-Balade B, Vandermoere F, Chagot ME, Hallais M, Ahmad Y, Leonhardt H,[...]
J Cell Biol. 207(4):463-80. Pubmed
SUMO2/3 modification of cyclin E contributes to the control of replication origin firing.
Bonne-Andrea C, Kahli M, Mechali F, Lemaitre JM, Bossis G, Coux O.
Nat Commun. 4:1850. Pubmed
Human Mob1 proteins are required for cytokinesis by controlling microtubule stability.
Florindo C, Perdigão J, Fesquet D, Schiebel E, Pines J, Tavares AA.
J Cell Sci. 125(Pt 13):3085-90. Pubmed
HIV-1, ubiquitin and ubiquitin-like proteins: the dialectic interactions of a virus with a sophisticated network of post-translational modifications.
Biard-Piechaczyk M, Borel S, Espert L, de Bettignies G, Coux O.
Biol Cell. 104(3):165-87. Pubmed
HSP90 and the R2TP co-chaperone complex: building multi-protein machineries essential for cell growth and gene expression.
Boulon S, Bertrand E, Pradet-Balade B.
RNA Biol. 9(2):148-54. Pubmed
An intranucleolar body associated with rDNA.
Hutten S, Prescott A, James J, Riesenberg S, Boulon S, Lam YW, Lamond AI.
Chromosoma. 120(5):481-99. Pubmed
Proteolytic activity and expression of the 20S proteasome are increased in psoriasis lesional skin.
Henry L, Le Gallic L, Garcin G, Coux O, Jumez N, Roger P, Lavabre-Bertrand T, Martinez J, Meunier L, Stoebner[...]
Br J Dermatol. 165(2):311-20. Pubmed
CRM1 controls the composition of nucleoplasmic pre-snoRNA complexes to licence them for nucleolar transport.
Pradet-Balade B, Girard C, Boulon S, Paul C, Azzag K, Bordonné R, Bertrand E, Verheggen C.
EMBO J. 30(11):2205-18. Pubmed
A capsid-encoded PPxY-motif facilitates adenovirus entry.
Wodrich H, Henaff D, Jammart B, Segura-Morales C, Seelmeir S, Coux O, Ruzsics Z, Wiethoff CM, Kremer EJ.
PLoS Pathog. 6(3):e1000808. Pubmed
Lessons from interconnected ubiquitylation and acetylation of p53: think metastable networks.
Benkirane M, Sardet C, Coux O.
Biochem Soc Trans. 38(Pt 1):98-103. Pubmed
Proteasome inhibitors: Dozens of molecules and still counting.
de Bettignies G, Coux O.
Biochimie. 92(11):1530-45. Pubmed
βTrCP-dependent degradation of CDC25B phosphatase at the metaphase-anaphase transition is a pre-requisite for correct mitotic exit.
Thomas Y, Coux O, Baldin V.
Cell Cycle. 9(21):4338-50. Pubmed
HSP90 and its R2TP/Prefoldin-like cochaperone are involved in the cytoplasmic assembly of RNA polymerase II.
Boulon S, Pradet-Balade B, Verheggen C, Molle D, Boireau S, Georgieva M, Azzag K, Robert MC, Ahmad Y, Neel H,[...]
Mol Cell. 39(6):912-924. Pubmed
High yield bacterial expression and purification of active recombinant PA28alphabeta complex.
Le Feuvre AY, Dantas-Barbosa C, Baldin V, Coux O.
Protein Expr Purif. 2009 Apr;64(2):219-24. Pubmed
JunB breakdown in mid-/late G2 is required for down-regulation of cyclin A2 levels and proper mitosis.
Farràs R, Baldin V, Gallach S, Acquaviva C, Bossis G, Jariel-Encontre I, Piechaczyk M.
Mol Cell Biol. 28(12):4173-87. Pubmed
A novel role for PA28gamma-proteasome in nuclear speckle organization and SR protein trafficking.
Baldin V, Militello M, Thomas Y, Doucet C, Fic W, Boireau S, Jariel-Encontre I, Piechaczyk M, Bertrand E, Tazi J,[...]
Mol Biol Cell. 19(4):1706-16. Pubmed
The Ubiquitin-Proteasome System
The ubiquitin-proteasome system (UPS) is an extremely complex multienzymatic system, which schematically functions in two distinct steps in the regulated degradation of intracellular proteins.
In a first step, the protein substrate is tagged by covalent addition of a chain formed by the successive conjugation of one or several ubiquitin (Ub) molecule(s), thanks to an enzymatic cascade involving three types of factors named E1 (Ub-activating enzyme), E2 (Ub-conjugating enzyme) and E3 (Ub-ligase). The specificity of the reaction (called ubiquitylation reaction) is mainly due to the E3s, which are responsible for substrate recruitment. Accordingly, numerous (several hundreds) E3-ligases exist in cells. Many de-ubiquitylation enzymes (about 100 in humans) are able to remove the Ub-chain from the substrates, and thus participate to the fine tuning of the ubiquitylation reaction.
In a second step, the poly-Ub chain is recognized by a giant protease called the 26S proteasome, which degrades the ubiquitylated protein into inactive peptides.
The 20S proteasome is a hollow cylinder-shaped protease, extremely conserved during evolution. It is formed by 28 subunits assembled in four rings of seven subunits each. The two outer rings are formed by α subunits, and the two inner rings by β subunits.
The catalytic sites are enclosed in an internal cavity defined by the β rings. Three types of peptidase activities are described: one chymotrypsin-like activity cleaving after hydrophobic residues, a trypsin-like acivity cleaving after basic residues and a caspase-like activity cleaving after acidic residues.
An important feature of the 20S proteasome is that it is weakly active by itself. Indeed, the catalytic sites are buried into the internal chamber formed by the β rings, and are thus only accessible through axial pores defined by the α subunits and closed by the N-terminal ends of these subunits. Consequently, substrate entry into the catalytic chamber requires the binding to the 20S proteasome of regulatory complexes that open the pores upon binding. A video illustrating this opening process (called 20S proteasome gate opening) upon the binding of a regulator (here PA28αβ, see below) has been realized by Geoffroy de Bettignies, a former member of our team (see the video here).
Thanks to the existence of different 20S proteasome regulators, the term ‘proteasome’ usually used in the scientific literature corresponds in reality to a family of protease complexes, which share a common proteolytic core (the 20S proteasome) but differ by the regulators bound to it. Among these regulators, the best known is the 19S complex or RP (for regulatory complex), which forms with the 20S proteasome the 26S proteasome responsible for the degradation of ubiquitylated proteins. Other regulators with ill-understood functions and mechanisms of action have been described: two nuclear complexes, PA28γ and PA200, and a cytoplasmic complex related to PA28γ and called PA28αβ.