Leiden University Scholarly Publications

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Jordens, Ingrid (2005)

Transport of Lysosome-Related Organelles

Doctoral Thesis
Many intracellular compartments, including (MHC class II-containing) lysosomes, melanosomes and phagosomes, move along microtubules in a bi-directional manner due to the alternating activities of the plus-end directed kinesin motor and the minus-end directed dynein-dynactin motor. However, it is largely unclear how these motor proteins are targeted to specific compartments. Rab GTPases recruit and/or activate several proteins involved in membrane fusion and vesicular transport. They associate with specific compartments and therefore are ideal candidates for controlling motor protein recruitment. This work shows that dynein-dynactin motor recruitment to lysosomal compartments requires activation of the GTPase Rab7 that subsequently associates with its effector protein, RILP (for Rab7-Interacting Lysosomal Protein). RILP maintains Rab7 in the vesicle-bound, activated state and transmits a signal for specific recruitment of the dynein-dynactin motor. As a consequence, lysosomes are...Show moreMany intracellular compartments, including (MHC class II-containing) lysosomes, melanosomes and phagosomes, move along microtubules in a bi-directional manner due to the alternating activities of the plus-end directed kinesin motor and the minus-end directed dynein-dynactin motor. However, it is largely unclear how these motor proteins are targeted to specific compartments. Rab GTPases recruit and/or activate several proteins involved in membrane fusion and vesicular transport. They associate with specific compartments and therefore are ideal candidates for controlling motor protein recruitment. This work shows that dynein-dynactin motor recruitment to lysosomal compartments requires activation of the GTPase Rab7 that subsequently associates with its effector protein, RILP (for Rab7-Interacting Lysosomal Protein). RILP maintains Rab7 in the vesicle-bound, activated state and transmits a signal for specific recruitment of the dynein-dynactin motor. As a consequence, lysosomes are transported towards the minus-end of microtubules. This signalling cascade thus regulates lysosomal transport. In addition, we showed that this pathway also regulates transport of several other lysosomal compartments, including Salmonella-containing vacuoles and melanosomes.Show less
MHC class II
Dynein
Kinesin
Rab GTPases
Myosin Va
Rab7
Rab27a
Salmonella
Dynactin
Microtubules
Late endosome
Lysosome
Melanosome
Phagosome
RILP
FRAP
Endocytosis
All authors
Jordens, Ingrid
Supervisor
Neefjes, J.J.
Qualification
Doctor (dr.)
Awarding Institution
Deptartment of Immunohematology and blood transfusion, Faculty of Medicine, Leiden University Medical Center (LUMC), Leiden University
Date
2005-11-23

Funding

Sponsorship
The work descripted in this thesis was performed at the Division of Tumor Biology of the Netherlands Cancer Institute, Amsterdam, The Netherlands and sponsored by the Koningin Wilhelmina Fonds and the Netherlands Organisation for Scientific Research NWO. KWF; NWO