Graham Warren, Ph.D.

Professor of Cell Biology Affiliate Member, Ludwig Institute for Cancer Research
Phone: (203) 785-5058 Lab: (203) 737-2610/2613 Fax: (203) 785-4301 Assistant: (203) 737-5690 e-mail: graham.warren@yale.edu		Department of Cell Biology Yale University School of Medicine 333 Cedar Street PO Box 208002 New Haven, CT 06520-8002 <Courier Address> 333 Cedar Street, SHM C-441 New Haven, CT 06510-3206

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We are studying the Golgi apparatus, which receives the entire output of newly-synthesized proteins and lipids from the endoplasmic reticulum, processes them in the stacked cisternae and then distributes them to their correct destination either inside or outside the cell.

In particular we are focusing on the biogenesis of this organelle, the process of duplication and partitioning between daughter cells [Shorter, 2002 #1]. Partitioning in animal cells involves fragmentation of the Golgi ribbon of linked stacks, dispersal of the fragments and reassembly in each daughter cell (Fig. 1, control) [Jokitalo, 2001; Seemann, 2002]. Reconstitution of this process in vitro (Fig. 2) helped us understand the process of intra-Golgi transport mediated by COPI-coated vesicles [Shorter, 2002; Müller, 2002] and, more recently, the role played by ubiquitination in the reassembly process mediated by the ATPase, p97 [Meyer, 2002].

These studies also led to the idea of the Golgi as an autonomous organelle with an underlying matrix of scaffolding proteins that helps determine its unique architecture and function [Seemann, 2000]. This matrix also mediates aspects of Golgi biogenesis [Pelletier, 2000], such as partitioning between daughter cells, even in the absence of the enzyme-containing membranes that normally populate these structures (Fig. 1, + BFA) [Seemann, 2002]. We are currently testing their role in the duplication of the Golgi apparatus, using protozoan parasites which offer the simplicity of a single Golgi stack. As shown in Fig. 3, in Toxoplasma gondii, this single Golgi grows by a process of lateral extension, followed by medial fission [Pelletier, 2002]. Complementary studies using Trypanosoma brucei should allow us to identify the core mechanism for duplication and partitioning of this cellular organelle.

Fig. 1. Partitioning of the Golgi matrix in animal cells in the absence (control) or presence of Brefeldin A (+BFA). [Seemann, 2002 (PDF)]

 

Fig. 2. Mitotic disassembly and reassembly of Golgi stacks in a cell-free system. [Shorter, 2002 (PDF)]

 

Fig. 3. Biogenesis of the Golgi apparatus in Toxoplasma gondii.
[Pelletier, 2002 (PDF)]
<QuickTime movie - click here or the image - 3.4MB >

Fig. 4. Biogenesis of the Golgi apparatus in Toxoplasma gondii. 3D reconstruction of two parasites during mitosis.
[Pelletier, 2002 (PDF)]
<QuickTime movie - click here or the image - 31.3MB >

 

Selected Publications

Click for PDF

Seemann J, Jokitalo E, Pypaert M, Warren G. (2000) Matrix proteins can generate the higher order architecture of the Golgi apparatus. Nature. 407(6807): 1022-6.

Pelletier L, Jokitalo E, Warren G. (2000) The effect of Golgi depletion on exocytic transport. Nat Cell Biol. 2(11): 840-6.

Jokitalo E, Cabrera-Poch N, Warren G, Shima DT. (2001) Golgi clusters and vesicles mediate mitotic inheritance independently of the endoplasmic reticulum. J Cell Biol. 154(2): 317-30.

Seemann J, Pypaert M, Taguchi T, Malsam J, Warren G. (2002) Partitioning of the matrix fraction of the Golgi apparatus during mitosis in animal cells. Science. 295(5556): 848-51.

Shorter J, Beard MB, Seemann J, Dirac-Svejstrup AB, Warren G. (2002) Sequential tethering of Golgins and catalysis of SNAREpin assembly by the vesicle-tethering protein p115. J Cell Biol. 157(1): 45-62.

Shorter J, Warren G. (2002) Golgi architecture and inheritance. Annu Rev Cell Dev Biol. 18: 379-420. [Review]

Pelletier L, Stern CA, Pypaert M, Sheff D, Ngô HM, Roper N, He CY, Hu K, Toomre D, Coppens I, Roos DS, Joiner KA, Warren G. (2002) Golgi biogenesis in Toxoplasma gondii. Nature. 418(6897): 548-52. [see Fig.3 & Fig.4 for movie downloads]

Meyer HH, Wang Y, Warren G. (2002) Direct binding of ubiquitin conjugates by the mammalian p97 adaptor complexes, p47 and Ufd1-Npl4. EMBO J. 21(21): 5645-52.

Wang Y, Seemann J, Pypaert M, Shorter J, Warren G. (2003) A direct role for GRASP65 as a mitotically regulated Golgi stacking factor. EMBO J. 22(13):3279-90.

Wang Y, Satoh A, Warren G, Meyer HH. (2004) VCIP135 acts as a deubiquitinating enzyme during p97-p47-mediated reassembly of mitotic Golgi fragments. J Cell Biol. 164(7): 973-8.

Axelsson MA, Warren G. (2004) Rapid, endoplasmic reticulum-independent diffusion of the mitotic Golgi haze. Mol Biol Cell. 15(4):1843-52.

He CY, Ho HH, Malsam J, Chalouni C, West CM, Ullu E, Toomre D, Warren G. (2004) Golgi duplication in Trypanosoma brucei. J Cell Biol. 165(3):313-21.

Wang Y, Satoh A, Warren G. (2004) Mapping the functional domains of the Golgi stacking factor GRASP65. J Biol Chem. 280(6):4921-8.

Malsam J*, Satoh A*, Pelletier L, Warren G. (2005) Golgin tethers define subpopulations of COPI vesicles. Science 307(5712):1095-8.

He CY, Pypaert M, Warren G. (2005) Golgi Duplication in Trypanosoma brucei Requires Centrin2. Science [Epub ahead of print]