Using innovative approaches such as phospholipid-specific antibodies and reconstituted cell-free systems, Jean Gruenberg and his colleagues were able to unravel several important mechanisms regulating the biogenesis and membrane dynamics of early and late endosomal compartments.
Biography
Jean Gruenberg was born in Switzerland in 1950.[citation needed] Jean Gruenberg is married to Françoise Gisou van der Goot, and they have two children Sébastien and a girl.1950.[citation needed] Jean Gruenberg and his family reside in Trelex Switzerland and he works at the University of Geneva as an emeritus professor in the Department of Biochemistry.
Scientific achievements
Cell-free reconstitution of endosomal fission and fusion events
After early studies on parasites (T. brucei and P. falciparum),[1][2] Jean Gruenberg switched focus and studied the dynamics endosomal processes when he started to work at the European Molecular Biology Laboratory (EMBL) with Kate Howell, and made several important discoveries on the molecular factors directing endosome dynamics, and was successful in reconstituting the process in vitro.[3][4][5][6] When he became an independent investigator, first at the EMBL and then at the University of Geneva, he continued this line of research and worked on the characterization of early and late endosomes, and identified a transport intermediate between these organelles known as the ECVs/MVBs (Early Carrier Vesicles / MultiVesicular Bodies).[7][8][9]
Molecular mechanisms of endosomal biogenesis and membrane dynamics
Throughout his career, Jean Gruenberg and his colleagues identified several molecular factors directing endosomal biogenesis and dynamics, including various cytoskeleton-associated proteins,[10][7][11] the small GTPases Rab5[12][13] and Rab7,[14] Annexin A2 (previously named Annexin II),[15][16][17][18][19][20] the vacuolar ATPase,[8] COP coat proteins,[21][22] the N-ethylmaleimide sensitive factor,[23] the small transmembrane proteins of the p24 family,[24][25][26][27] the p38 MAP kinase,[28] phosphatidylinositol-3-phosphate,[29] intra-endosomal cholesterol,[30][31] the redox sensor thioredoxin-like protein,[32] sorting nexins,[33][34][35] the adaptor protein complex AP1,[36] components of ESCRTs and associated proteins[37][33][38][39][40] and the atypical phospholipid LBPA/BMP (see next section).
Using the Vesicular Stomatitis Virus (VSV) as a “hijacker” of the endocytic pathway, Jean Gruenberg and his colleagues demonstrated that intralumenal vesicles present within multivesicular endosomes are able to undergo back-fusion with the limiting membrane of these organelles, thus releasing their content into the cytoplasm,[41] a process regulated by the ESCRT-related proteins TSG101[39] and ALIX,[42] and since shown to be exploited by various other invaders of the cells such as the Anthrax toxin,[43] and several other viruses.[44]
Characterization of lysobisphosphatidic acid using anti-phospholipid antibodies
A milestone discovery in the career of Jean Gruenberg was the identification and the characterization of an atypical inverted cone-shaped phospholipid,[45] originally named lysobisphosphatidic acid (LBPA) and also known as bis(monoacylglycero)phosphate (BMP). Using specific monoclonal antibodies, LBPA/BMP was shown to be enriched in intralumenal vesicles of late endosomes[46] and to regulate the intracellular transport and homeostasis of cholesterol.[47][31] LBPA/BMP is also directly involved in the formation of intracellular vesicles within multivesicular endosomes and endosome-mimicking liposomes.[37]
^Gruenberg, J.; Howell, K. E. (1988). "Fusion in the endocytic pathway reconstituted in a cell-free system using immuno-isolated fractions". Progress in Clinical and Biological Research. 270: 317–331. ISSN0361-7742. PMID3045833.
^Bomsel, M.; Parton, R.; Kuznetsov, S. A.; Schroer, T. A.; Gruenberg, J. (1990-08-24). "Microtubule- and motor-dependent fusion in vitro between apical and basolateral endocytic vesicles from MDCK cells". Cell. 62 (4): 719–731. doi:10.1016/0092-8674(90)90117-w. ISSN0092-8674. PMID2143699. S2CID31624175.
^Robinson, L. J.; Aniento, F.; Gruenberg, J. (1997). "NSF is required for transport from early to late endosomes". Journal of Cell Science. 110 ( Pt 17) (17): 2079–2087. doi:10.1242/jcs.110.17.2079. ISSN0021-9533. PMID9378758.
^Chevallier, J.; Sakai, N.; Robert, F.; Kobayashi, T.; Gruenberg, J.; Matile, S. (2000-06-29). "Rapid access to synthetic lysobisphosphatidic acids using P(III) chemistry". Organic Letters. 2 (13): 1859–1861. doi:10.1021/ol0059246. ISSN1523-7060. PMID10891176.
^Kobayashi, T.; Stang, E.; Fang, K. S.; de Moerloose, P.; Parton, R. G.; Gruenberg, J. (1998-03-12). "A lipid associated with the antiphospholipid syndrome regulates endosome structure and function". Nature. 392 (6672): 193–197. Bibcode:1998Natur.392..193K. doi:10.1038/32440. ISSN0028-0836. PMID9515966. S2CID4322776.
^Kobayashi, T.; Beuchat, M. H.; Lindsay, M.; Frias, S.; Palmiter, R. D.; Sakuraba, H.; Parton, R. G.; Gruenberg, J. (1999). "Late endosomal membranes rich in lysobisphosphatidic acid regulate cholesterol transport". Nature Cell Biology. 1 (2): 113–118. doi:10.1038/10084. ISSN1465-7392. PMID10559883. S2CID15948485.
