Endosome maturation - PubMed (original) (raw)
Review
Endosome maturation
Jatta Huotari et al. EMBO J. 2011.
Abstract
Being deeply connected to signalling, cell dynamics, growth, regulation, and defence, endocytic processes are linked to almost all aspects of cell life and disease. In this review, we focus on endosomes in the classical endocytic pathway, and on the programme of changes that lead to the formation and maturation of late endosomes/multivesicular bodies. The maturation programme entails a dramatic transformation of these dynamic organelles disconnecting them functionally and spatially from early endosomes and preparing them for their unidirectional role as a feeder pathway to lysosomes.
Conflict of interest statement
The authors declare that they have no conflict of interest.
Figures
Figure 1
The basic elements of the endocytic machinery. The membrane organelles involve a recycling circuit (the plasma membrane (PM), the EEs, the recycling endosomes, and a variety vesicular carriers), a degradation cycle (lysosomes), and a connecting ‘_feeder_’ pathway (LEs) from the recycling circuit to the degradative system. The main interacting partner in the Golgi providing lysosomal components is the TGN, which communicates with the PM, EEs and LEs. The recycling circuit has functions independent of the degradative cycle. The degradative cycle is, in turn, a shared ‘facility’ for degradation in the cell and is not only used for substrates delivered via endosomes. The cytosol has a central role by providing peripheral proteins to all the membrane compartments. These proteins define functions such as molecular sorting, membrane fusion and fission, compartment identity, and organelle motility.
Figure 2
The endosome/lysosome system. The primary endocytic vesicles deliver their contents and their membrane to EEs in the peripheral cytoplasm. After a period of about 8–15 min during which the EEs accumulate cargo and support recycling to the plasma membrane (directly or via recycling endosomes in the perinuclear region), conversion of the EEs to LE takes place. Thus, as the endosomes are moving towards the perinuclear space along microtubules (MT), the nascent LE are formed inheriting the vacuolar domains of the EE network. They carry a selected subset of endocytosed cargo from the EE, which they combine en route with newly synthesized lysosomal hydrolases and membrane components from the secretory pathway. They undergo homotypic fusion reactions, grow in size, and acquire more ILVs. Their role as feeder system is to deliver this mixture of endocytic and secretory components to lysosomes. To be able to do it, they continue to undergo a maturation process that prepares them for the encounter with lysosomes. The fusion of an endosome with a lysosome generates a transient hybrid organelle, the endolysosome, in which active degradation takes place. What follows is another maturation process; the endolysosome is converted to a classical dense lysosome, which constitutes a storage organelle for lysosomal hydrolases and membrane components.
Figure 3
Morphologies of endosomes and lysosomes at the ultrastructural level. (A) Electron micrographs of peripherally located EEs containing HRP-conjugated Tf. They contain vacuolar and tubular domains. Courtesy of Tooze and Hollinshead (1992). Electron micrographs of (B) EE with clathrin lattices and a few ILVs; (C) LE, containing numerous ILVs; (D) endolysosome, with partial electron dense areas; and (E) lysosomes, with electron dense lumen. Images are all from HeLa cells that had been processed for thin section EM. Scale bars in (A): 500 nm and (B–E): 100 nm. Figure 3A is reproduced with kind permission from Rockefeller University Press;©2009 Rockefeller University Press. Originally published in J Cell Biol 118: 813–830. doi: 10.1083/jcb.118.4.813.
Figure 4
The Rab5/Rab7 switch during endosome maturation. Normally, Rab5-GDP and Rab7-GDP reside in the cytosol bound to its GDI. Rab5 is activated to its GTP-bound and membrane-associated form by the GEF Rabex-5 on EE membranes. The Rab5 effector Rabaptin-5 binds to Rabex-5 and promotes the activation of Rab5, thus forming a positive feedback loop in which more Rab5 molecules are activated and recruited. To initiate the Rab switch, Mon1/SAND-1 complexed with Ccz1 binds to Rab5, PtdIns(3)P, and Rabex-5, causing disassociation of Rabex-5 from the membrane. This in turn terminates the feedback loop, resulting in Rab5 inactivation and disassociation. The Mon1/SAND-1–Ccz1 complex promotes (directly or indirectly) the recruitment and activation of Rab7. Members of the HOPS complex (Vps11, Vps16, Vps18, Vps33, Vps39, and Vps41) are able to bind both Rab7 and the Mon1/SAND-1–Ccz1 complex. The HOPS complex mediates membrane tethering, needed for fusion with other LEs and lysosomes. Adapted from Cabrera and Ungermann (2010).
Figure 5
Phosphatidylinositide regulation on endosomes. On EEs, PtdIns(3)P is synthesized by the kinase VPS34, which forms a core complex together with p150 and Beclin-1. The complex binds on endosomes to UVRAG (Itakura et al, 2008), which is normally inhibited by a Rab7 effector, Rubicon (Sun et al, 2010). Once activated, Rab7 sequesters Rubicon from UVRAG, allowing it to activate the HOPS complex. Dephosphorylation of PtdIns(3)P is catalyzed by members of the Myotubularin family. The kinase responsible for conversion of PtdIns(3)P to PtdIns(3,5)P(2) is PIKfyve (Fab1p) (Gary et al, 1998; Ikonomov et al, 2002). It forms an active complex with its activator ArPIKfyve (Vac14p) and the phosphatase Sac3 (Fig4p). This complex is required for both the kinase and the phosphatase activities (Sbrissa et al, 2008; Ikonomov et al, 2009).
Figure 6
LE motility. (A) LEs are transported on microtubules (MT) in a bidirectional manner, by the help of both kinesin and dynein motor proteins. Net movement is towards the microtubule organizing centre (MTOC), located in the perinuclear region of the cell, where most of the LEs and lysosomes localize. (B) Schematic of LE attachment to dynein motor through RILP. Activated Rab7 binds to its effectors RILP and ORP1L. Homodimeric RILP then recruits dynein–dynactin motor complex through the p150(Glued) subunit. The complex has to additionally interact with the dynein membrane receptor βIII spectrin (Johansson et al, 2007). This allows transport of cargo towards the MTOC. In the presence of low cholesterol on LE membranes, sensed by ORP1L, the complex is disassembled due to a conformational change of ORP1L, and resulting in inhibition of motility towards the MTOC (Rocha et al, 2009).
Figure 7
Function of LEs. (A) Cargo that needs to degraded is endocytosed and sorted into ILVs. This can be also used to silence signalling from receptors, normally exposed to the cytosol. (B) Microautophagy is used to bring cytosolic contents into LEs. (C) ILVs can be secreted as exosomes to the extracellular environment upon fusion of LEs with the plasma membrane. (D) ‘Backfusion’ of ILVs with the limiting membrane of LEs allows retrieval of membrane cargo or release of ILV contents into the cytosol.
References
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