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Endocytosis and Exocytosis

Introduction

One of the important things to remember about cells is that they are dynamic. If you look at a cell under a live microscope you'll see areas which are constantly moving.

Much of this movement is to regulate the contents of the cell. This includes bringing material into the cell from the extracellular environment or the plasma membrane (endocytosis) or releasing material made within the the cell to the outside (exocytosis).

Endocytosis

Endocytosis is primarily involved in removing receptors from the cell surface and taking them to be destroyed. This is an important process because it ends the signal from the receptor. The stages of endocytosis are helpfully explained in the figures below, but here's a summary:

  • The ligand binds to its receptor and this generates a signal. This signal leads to a response from the cell.
  • The receptor is tagged by a protein called ubiquitin. This means that the receptor has been marked for internalisation.
  • A protein complex called clathrin assembles around the receptor and brings it into the cell inside a clathrin-coated vesicle.
  • The vesicle with the receptor inside encounters an endosome, a membranous organelle designed to sort between receptors which can be recycled back to the plasma membrane and those which need to be destroyed.
  • If the receptor is to be destroyed, it is placed inside a vesicle within the endosome. A set of protein complexes called Endosomal Sorting Complex Required for Transport (ESCRT)s are responsible for recognising a receptor which is to be destroyed and forming the vesicle around it. 
  • Receptors which are to be recycled are kept out of these internal vesicles.
  • An endosome which contains receptors inside vesicles is known as a Multivesicular Body (MVB).
  • The MVB travels towards the centre of the cell and encounters a lysosome. This is another membranous organelle which contains enzymes to destroy the receptor. Receptors which are to be recycled have their ligand removed and are released from the MVB back to the plasma membrane.
  • The receptors inside the vesicles are delivered to the lysosome and are destroyed by the enzymes. The signal is ended.

 

Most receptors will follow either the recycling pathway or the degradation pathway, although not in 100% of cases. An example of a receptor which is usually recycled is the Transferrin Receptor (TfR). A receptor which is usually degraded is the Epidermal Growth Factor Receptor (EGFR).

Endocytosis Stage 1: Signalling and Ubiquitin tagging



Endocytosis Stage 2: Internalisation and MVB formation



Endocytosis Stage 3: Delivery to Lysosome and Receptor Degradation



How endocytosis is like being a dustman

Endocytosis

  • The unwanted material (receptor) is marked for degradation by addition of ubiquitin.
  • The marked material is taken away to an area where they will be sorted.
  • The endosome distinguishes between receptors which need to be recycled and those which need to be destroyed.
  • The receptor is destroyed by the lysosome.

Dustman

  • The unwanted material is signalled for destruction by putting it in the bin.
  • The rubbish is collected by the Dustman and taken to the dump.
  • Recyclable material is removed and sorted, other rubbish is taken to the incinerator.
  • The rubbish is destroyed by incineration.

Endocytosis and disease

There could be a link between endocytosis and cancer. Some receptors, such as the EGFR, are responsible for transducing (converting) the signal from growth factors. As the name suggests, these factors trigger cell growth. Endocytosis is responsible for ending the signal (also known as signal attenuation) by removing the ligand and destroying the receptor. If the signal is not stopped, the cell will be told to grow indefinitely. This could lead to cancer, which occurs when cells grow and divide out of control.

The endocytic machinery is also used by certain viruses such as human immunodeficiency virus (HIV). These viruses hijack the ESCRT proteins and use them for their own nefarious purposes! The virus uses the ESCRTs to help release copies of itself from the infected (host) cell, and these copies will go on to infect neighbouring cells.

Exocytosis

Exocytosis is (unsurprisingly) the opposite of endocytosis. This is when material which has been made inside the cell is released into the extracellular environment. 

Many proteins are synthesised in the cell cytoplasm. However, if they are destined to be released from the cell, they may pass through the secretory pathway. These proteins are made at the membrane of the rough endoplasmic reticulum, so called as it has the protein-making ribosomes attached to its surface.

The protein will then be packaged into a vesicle and  delivered to the Golgi apparatus, which can make several modifications to the protein along the way. 

After passing through the Golgi apparatus, the protein may be enclosed within another vesicle which pinches off and travels towards the plasma membrane. This vesicle then docks and fuses with the plasma membrane with the aid of a group of proteins called SNARE complexes. This will involve a specifc SNARE complex on the vesicle (called a v-SNARE) binding to a specific SNARE complex on the plasma membrane (called the t-SNARE or "target SNARE"). These SNARES are highly specific to allow correct delivery of the contents to the right compartment. Different combinations of v- and t- SNARE complexes are responsible for targeting different vesicles to a specific cell compartment - e.g. the Golgi to the plasma membrane in exocytosis, or the endoplasmic reticulum to the Golgi.

Another set of proteins called Rab proteins are thought to help to make sure the vesicle docking is specific. Certain Rab members are specific to each compartment membrane, e.g. Rab5A is found on the plasma membrane, Rab2 is found on the Golgi. Rab proteins are GTPases, meaning they require the nucleotide GTP to activate them.

Once the vesicle has fused to the plasma membrane, the cell can then release its content to the extracellular environment.

Exocytosis Stage 1: Protein translation



Exocytosis Stage 2: The Secretory Pathway



Exocytosis Stage 3: Docking, Fusion and Release



Exocytosis examples

  • Nerve cells: a nerve cell will release a neurotransmitter (such as serotonin or dopamine) into the space between two nerve cells (the synapse) via exocytosis. This will help to transmit the nerve signal. This is called Regulated Exocytosis as it only occurs in response to a specific event.
  • Pancreatic beta-cell: In response to the body ingesting something containing glucose, the beta cells in the pancreas will release insulin via exocytosis. This is another example of regulated exocytosis.
  • Fibroblasts: This cell type is responsible for the extracellular matrix which forms structural support for the cells in the human body. Therefore fibroblasts constantly release substances into the matrix such as collagen (known as constitutive exocytosis).

References

Alberts et al Molecular Biology of the Cell p.721-723, p.749-756. 4th Edition (2002) Garland Science.

Piper and Katzmann (2007) Biogenesis and Function of Multivesicular Bodies Annu. Rev. Cell Dev. Biol. 23:519–47

Mosesson et al (2008) Derailed Endocytosis: an emerging feature of cancer Nat Rev Cancer 8(11):835-50.

http://www.ncbi.nlm.nih.gov/books/NBK21471/ Overview of the Secretory Pathway, fromLodish H et al, Molecular Cell Biology. 4th edition (2000), W. H. Freeman

Schiavo et al (1997) Binding of the synaptic vesicle v-SNARE, synaptotagmin, to the plasma membrane t-SNARE, SNAP25, can explain docked vesicles at neurotoxin-treated synapses Proc. Natl. Acad. Sci. USA 94:997–1001

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