This thesis provides new insights in the regulation of late endosomal and lysosomal transport. We show the involvement of the Rab7/RILP/dynein pathway in the intracellular retention of late endosomal and lysosomal compartments like MIIC, phagosomes and melanosomes. The key question remains what regulates transport in the opposite (+ end) direction. Is it regulated directly or depending on the inactivation of the Rab7/RILP pathway? The rapid redistribution of late endocytic structures into the periphery upon disruption of dynein motor function supports the latter case. Thus by stimulating the Rab7/RILP pathway, contents of lysosomes can be kept intracellular. It has been shown that the cytokine IL-10 largely reduces cell surface expression of MHC class II molecules by inhibiting transport of MIIC to the membrane [66], analogous to the effect of RILP. Several tumours secrete IL-10, most likely to reduce antigen presentation [67,68]. Interestingly, RILP mRNA levels are highly upregulated in monocytes treated with IL-10 (our unpublished data). This suggests that RILP-dependent retention of MIIC is, at least in part, responsible for the reduced antigen presentation by MHC class II molecules. Moreover, we have shown that activation of the Rab7/RILP pathway reduces the intracellular survival of Salmonella (Chapter 5). Thus the Rab7/RILP pathway might be an interesting target for manipulation in many different diseases in which transport and fusion of late endocytic structures like MIIC, phagosomes or secretory vesicles are involved.
Chapter 7
References
1. Wubbolts R, Neefjes J: Intracellular transport and peptide loading of MHC class II molecules:
regulation by chaperones and motors.Immunol Rev 1999, 172: 189-208.
2. Wubbolts RW, Fernandez-Borja M, Oomen L, Verwoerd D, Janssen H, Calafat J et al.: Direct
vesicular transport of MHC class II molecules from lysosomal structures to the cell surface.J Cell
Biol 1996, 135: 611-622.
3. Raposo G, Nijman HW, Stoorvogel W, Liejendekker R, Harding CV, Melief CJ et al.: B lymphocytes secrete antigen-presenting vesicles.J Exp Med 1996, 183: 1161-1172.
4. Boes M, Cerny J, Massol R, Op dB, Kirchhausen T, Chen J et al.: T-cell engagement of dendritic cells
rapidly rearranges MHC class II transport.Nature 2002, 418: 983-988.
5. Chow A, Toomre D, Garrett W, Mellman I: Dendritic cell maturation triggers retrograde MHC
class II transport from lysosomes to the plasma membrane.Nature 2002, 418: 988-994.
6. Kleijmeer M, Ramm G, Schuurhuis D, Griffith J, Rescigno M, Ricciardi-Castagnoli P et al.:
Reorganization of multivesicular bodies regulates MHC class II antigen presentation by dendritic cells.J Cell Biol 2001, 155: 53-63.
7. Goldstein LS: Molecular motors: from one motor many tails to one motor many tales.Trends Cell Biol 2001, 11: 477-482.
8. Hirokawa N: Kinesin and dynein superfamily proteins and the mechanism of organelle transport. Science 1998, 279: 519-526.
9. Bananis E, Nath S, Gordon K, Satir P, Stockert RJ, Murray JW et al.: Microtubule-dependent
movement of late endocytic vesicles in vitro: requirements for Dynein and Kinesin.Mol Biol Cell
2004, 15: 3688-3697.
10. Wubbolts R, Fernandez-Borja M, Jordens I, Reits E, Dusseljee S, Echeverri C et al.: Opposing motor activities of dynein and kinesin determine retention and transport of MHC class II-containing compartments.J Cell Sci 1999, 112 ( Pt 6): 785-795.
11. Santama N, Krijnse-Locker J, Griffiths G, Noda Y, Hirokawa N, Dotti CG: KIF2beta, a new kinesin superfamily protein in non-neuronal cells, is associated with lysosomes and may be implicated in their centrifugal translocation.EMBO J 1998, 17: 5855-5867.
12. Lee KD, Hollenbeck PJ: Phosphorylation of kinesin in vivo correlates with organelle association and neurite outgrowth.J Biol Chem 1995, 270: 5600-5605.
13. Marlowe KJ, Farshori P, Torgerson RR, Anderson KL, Miller LJ, McNiven MA: Changes in kinesin
distribution and phosphorylation occur during regulated secretion in pancreatic acinar cells.Eur
J Cell Biol 1998, 75: 140-152.
14. Matthies HJ, Miller RJ, Palfrey HC: Calmodulin binding to and cAMP-dependent phosphorylation
of kinesin light chains modulate kinesin ATPase activity.J Biol Chem 1993, 268: 11176-11187.
15. Sato-Yoshitake R, Yorifuji H, Inagaki M, Hirokawa N: The phosphorylation of kinesin regulates its binding to synaptic vesicles.J Biol Chem 1992, 267: 23930-23936.
16. Deacon SW, Serpinskaya AS, Vaughan PS, Lopez FM, Vernos I, Vaughan KT et al.: Dynactin is required for bidirectional organelle transport.J Cell Biol 2003, 160: 297-301.
17. Holzbaur EL, Vallee RB: DYNEINS: molecular structure and cellular function.Annu Rev Cell Biol 1994, 10: 339-372.
18. Paschal BM, Shpetner HS, Vallee RB: MAP 1C is a microtubule-activated ATPase which
translocates microtubules in vitro and has dynein-like properties. J Cell Biol 1987, 105: 1273-
1282.
19. Niclas J, Allan VJ, Vale RD: Cell cycle regulation of dynein association with membranes modulates microtubule-based organelle transport.J Cell Biol 1996, 133: 585-593.
20. Vaughan PS, Leszyk JD, Vaughan KT: Cytoplasmic dynein intermediate chain phosphorylation regulates binding to dynactin.J Biol Chem 2001, 276: 26171-26179.
21. Rogers SL, Tint IS, Fanapour PC, Gelfand VI: Regulated bidirectional motility of melanophore
pigment granules along microtubules in vitro.Proc Natl Acad Sci U S A 1997, 94: 3720-3725.
22. Kumar S, Lee IH, Plamann M: Cytoplasmic dynein ATPase activity is regulated by dynactin-
dependent phosphorylation.J Biol Chem 2000, 275: 31798-31804.
23. Kural C, Kim H, Syed S, Goshima G, Gelfand VI, Selvin PR: Kinesin and dynein move a peroxisome
in vivo: a tug-of-war or coordinated movement?Science 2005, 308: 1469-1472.
Chapter 7
25. Meresse S, Gorvel JP, Chavrier P: The rab7 GTPase resides on a vesicular compartment connected to lysosomes.J Cell Sci 1995, 108 ( Pt 11): 3349-3358.
26. Vitelli R, Santillo M, Lattero D, Chiariello M, Bifulco M, Bruni CB et al.: Role of the small GTPase Rab7 in the late endocytic pathway.J Biol Chem 1997, 272: 4391-4397.
27. Cantalupo G, Alifano P, Roberti V, Bruni CB, Bucci C: Rab-interacting lysosomal protein (RILP):
the Rab7 effector required for transport to lysosomes.EMBO J 2001, 20: 683-693.
28. Jordens I, Fernandez-Borja M, Marsman M, Dusseljee S, Janssen L, Calafat J et al.: The Rab7 effector protein RILP controls lysosomal transport by inducing the recruitment of dynein-dynactin motors.Curr Biol 2001, 11: 1680-1685.
29. Holleran EA, Ligon LA, Tokito M, Stankewich MC, Morrow JS, Holzbaur EL: BetaIII spectrin binds
to the Arp1 subunit of dynactin.J Biol Chem 2001.
30. Muresan V, Stankewich MC, Steffen W, Morrow JS, Holzbaur EL, Schnapp BJ: Dynactin-Dependent, Dynein-Driven Vesicle Transport in the Absence of Membrane Proteins. A Role for Spectrin and Acidic Phospholipids.Mol Cell 2001, 7: 173-183.
31. Hoepfner S, Severin F, Cabezas A, Habermann B, Runge A, Gillooly D et al.: Modulation of receptor
recycling and degradation by the endosomal kinesin KIF16B.Cell 2005, 121: 437-450.
32. Seabra MC, Coudrier E: Rab GTPases and myosin motors in organelle motility. Traffic 2004, 5:
393-399.
33. Chabrillat ML, Wilhelm C, Wasmeier C, Sviderskaya EV, Louvard D, Coudrier E: Rab8 Regulates the
Actin-based Movement of Melanosomes.Mol Biol Cell 2005.
34. Fukuda M, Kuroda TS, Mikoshiba K: Slac2-a/melanophilin, the missing link between Rab27 and
myosin Va: implications of a tripartite protein complex for melanosome transport.J Biol Chem
2002, 277: 12432-12436.
35. Hume AN, Collinson LM, Hopkins CR, Strom M, Barral DC, Bossi G et al.: The leaden gene product
is required with Rab27a to recruit myosin Va to melanosomes in melanocytes. Traffic 2002, 3:
193-202.
36. Nagashima K, Torii S, Yi Z, Igarashi M, Okamoto K, Takeuchi T et al.: Melanophilin directly links
Rab27a and myosin Va through its distinct coiled-coil regions.FEBS Lett 2002, 517: 233-238.
37. Westbroek W, Lambert J, Bahadoran P, Busca R, Herteleer MC, Smit N et al.: Interactions of human Myosin Va isoforms, endogenously expressed in human melanocytes, are tightly regulated by the tail domain.J Invest Dermatol 2003, 120: 465-475.
38. Wu X, Rao K, Bowers MB, Copeland NG, Jenkins NA, Hammer JA, III: Rab27a enables myosin Va-
dependent melanosome capture by recruiting the myosin to the organelle. J Cell Sci 2001, 114:
1091-1100.
39. Gomez PF, Luo D, Hirosaki K, Shinoda K, Yamashita T, Suzuki J et al.: Identification of rab7 as a melanosome-associated protein involved in the intracellular transport of tyrosinase-related protein 1.J Invest Dermatol 2001, 117: 81-90.
40. Hirosaki K, Yamashita T, Wada I, Jin HY, Jimbow K: Tyrosinase and tyrosinase-related protein 1 require Rab7 for their intracellular transport.J Invest Dermatol 2002, 119: 475-480.
41. Gross SP, Tuma MC, Deacon SW, Serpinskaya AS, Reilein AR, Gelfand VI: Interactions and
regulation of molecular motors in Xenopus melanophores.J Cell Biol 2002, 156: 855-865.
42. Araki K, Horikawa T, Chakraborty AK, Nakagawa K, Itoh H, Oka M et al.: Small Gtpase rab3A is
associated with melanosomes in melanoma cells.Pigment Cell Res 2000, 13: 332-336.
43. Yi Z, Yokota H, Torii S, Aoki T, Hosaka M, Zhao S et al.: The Rab27a/granuphilin complex
regulates the exocytosis of insulin-containing dense-core granules. Mol Cell Biol 2002, 22: 1858-
1867.
44. Fukuda M: Distinct Rab binding specificity of Rim1, Rim2, rabphilin, and Noc2. Identification of a
critical determinant of Rab3A/Rab27A recognition by Rim2.J Biol Chem 2003, 278: 15373-15380.
45. Knodler LA, Steele-Mortimer O: Taking possession: biogenesis of the Salmonella-containing vacuole.Traffic 2003, 4: 587-599.
46. Meresse S, Steele-Mortimer O, Moreno E, Desjardins M, Finlay B, Gorvel JP: Controlling the
maturation of pathogen-containing vacuoles: a matter of life and death. Nat Cell Biol 1999, 1:
E183-E188.
47. Guignot J, Caron E, Beuzon C, Bucci C, Kagan J, Roy C et al.: Microtubule motors control
membrane dynamics of Salmonella-containing vacuoles.J Cell Sci 2004, 117: 1033-1045.
48. Meresse S, Steele-Mortimer O, Finlay BB, Gorvel JP: The rab7 GTPase controls the maturation of
Chapter 7
49. Raffatellu M, Wilson RP, Chessa D, Andrews-Polymenis H, Tran QT, Lawhon S et al.: SipA, SopA, SopB, SopD, and SopE2 contribute to Salmonella enterica serotype typhimurium invasion of epithelial cells.Infect Immun 2005, 73: 146-154.
50. Waterman SR, Holden DW: Functions and effectors of the Salmonella pathogenicity island 2 type III secretion system.Cell Microbiol 2003, 5: 501-511.
51. Williams C, Galyov EE, Bagby S: solution structure, backbone dynamics, and interaction with
Cdc42 of Salmonella guanine nucleotide exchange factor SopE2. Biochemistry 2004, 43: 11998-
12008.
52. Harrison RE, Brumell JH, Khandani A, Bucci C, Scott CC, Jiang X et al.: Salmonella impairs RILP
recruitment to Rab7 during maturation of invasion vacuoles.Mol Biol Cell 2004, 15: 3146-3154.
53. Wang T, Wong KK, Hong W: A unique region of RILP distinguishes it from its related proteins in
its regulation of lysosomal morphology and interaction with Rab7 and Rab34.Mol Biol Cell 2004,
15: 815-826.
54. Wu M, Wang T, Loh E, Hong W, Song H: Structural basis for recruitment of RILP by small
GTPase Rab7.EMBO J 2005, 24: 1491-1501.
55. Colucci AM, Campana MC, Bellopede M, Bucci C: The Rab-interacting lysosomal protein, a Rab7
and Rab34 effector, is capable of self-interaction. Biochem Biophys Res Commun 2005, 334: 128-
133.
56. Caplan S, Hartnell LM, Aguilar RC, Naslavsky N, Bonifacino JS: Human Vam6p promotes lysosome clustering and fusion in vivo.J Cell Biol 2001, 154: 109-122.
57. Poupon V, Stewart A, Gray SR, Piper RC, Luzio JP: The role of mVps18p in clustering, fusion, and intracellular localization of late endocytic organelles.Mol Biol Cell 2003, 14: 4015-4027.
58. Huizing M, Didier A, Walenta J, Anikster Y, Gahl WA, Kramer H: Molecular cloning and
characterization of human VPS18, VPS 11, VPS16, and VPS33.Gene 2001, 264: 241-247.
59. Richardson SC, Winistorfer SC, Poupon V, Luzio JP, Piper RC: Mammalian late vacuole protein
sorting orthologues participate in early endosomal fusion and interact with the cytoskeleton.Mol
Biol Cell 2004, 15: 1197-1210.
60. Sato TK, Rehling P, Peterson MR, Emr SD: Class C Vps protein complex regulates vacuolar
SNARE pairing and is required for vesicle docking/fusion.Mol Cell 2000, 6: 661-671.
61. Wurmser AE, Sato TK, Emr SD: New component of the vacuolar class C-Vps complex couples
nucleotide exchange on the Ypt7 GTPase to SNARE-dependent docking and fusion. J Cell Biol
2000, 151: 551-562.
62. Woodman PG: Biogenesis of the sorting endosome: the role of Rab5.Traffic 2000, 1: 695-701. 63. Stein MP, Feng Y, Cooper KL, Welford AM, Wandinger-Ness A: Human VPS34 and p150 are Rab7
interacting partners.Traffic 2003, 4: 754-771.
64. Mizuno K, Kitamura A, Sasaki T: Rabring7, a novel Rab7 target protein with a RING finger motif. Mol Biol Cell 2003, 14: 3741-3752.
65. Nielsen E, Severin F, Backer JM, Hyman AA, Zerial M: Rab5 regulates motility of early endosomes on microtubules.Nat Cell Biol 1999, 1: 376-382.
66. Koppelman B, Neefjes JJ, de Vries JE, de Waal MR: Interleukin-10 down-regulates MHC class II alphabeta peptide complexes at the plasma membrane of monocytes by affecting arrival and recycling.Immunity 1997, 7: 861-871.
67. Benjamin D, Knobloch TJ, Dayton MA: Human B-cell interleukin-10: B-cell lines derived from patients with acquired immunodeficiency syndrome and Burkitt's lymphoma constitutively secrete large quantities of interleukin-10.Blood 1992, 80: 1289-1298.
68. Dummer W, Bastian BC, Ernst N, Schanzle C, Schwaaf A, Brocker EB: Interleukin-10 production in malignant melanoma: preferential detection of IL-10-secreting tumor cells in metastatic lesions. Int J Cancer 1996, 66: 607-610.