The endoplasmic reticulum (ER) is, in essence, the transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle
made up of two subunits – rough endoplasmic reticulum (RER), and smooth endoplasmic reticulum (SER). The endoplasmic reticulum is found in most eukaryotic cells
and forms an interconnected network of flattened, membrane-enclosed sacs known as cisterna
e (in the RER), and tubular structures in the SER. The membranes of the ER are continuous with the outer nuclear membrane
. The endoplasmic reticulum is not found in red blood cell
s, or spermatozoa
The two types of ER share many of the same proteins
and engage in certain common activities such as the synthesis of certain lipids
. Different types of cells
contain different ratios of the two types of ER depending on the activities of the cell.
The outer (cytosol
ic) face of the rough endoplasmic reticulum is studded with ribosome
s that are the sites of protein synthesis
. The rough endoplasmic reticulum is especially prominent in cells such as hepatocyte
s. The smooth endoplasmic reticulum lacks ribosomes and functions in lipid
synthesis but not metabolism
, the production of steroid hormone
s, and detoxification
The smooth endoplasmic reticulum is especially abundant in mammalian liver
The ER was observed with light microscope
by Garnier in 1897, who coined the term ''ergastoplasm''.
With electron microscopy
, the lacy membranes of the endoplasmic reticulum were first seen in 1945 by Keith R. Porter
, Albert Claude
, and Ernest F. Fullam.
Later, the word ''reticulum
'', which means "network", was applied by Porter in 1953 to describe this fabric of membranes.
3D rendering of endoplasmic reticulum
The general structure of the endoplasmic reticulum is a network of membranes called cisterna
e. These sac-like structures are held together by the cytoskeleton
. The phospholipid membrane
encloses the cisternal space (or lumen), which is continuous with the perinuclear space
but separate from the cytosol
. The functions of the endoplasmic reticulum can be summarized as the synthesis and export of proteins and membrane lipids, but varies between ER and cell type and cell function. The quantity of both rough and smooth endoplasmic reticulum in a cell can slowly interchange from one type to the other, depending on the changing metabolic activities of the cell. Transformation can include embedding of new proteins in membrane as well as structural changes. Changes in protein content may occur without noticeable structural changes.
Rough endoplasmic reticulum
The surface of the rough endoplasmic reticulum (often abbreviated ''RER'' or ''rough ER''; also called ''granular endoplasmic reticulum'') is studded with protein-manufacturing ribosome
s giving it a "rough" appearance (hence its name). The binding site of the ribosome on the rough endoplasmic reticulum is the translocon
. However, the ribosomes are not a stable part of this organelle's structure as they are constantly being bound and released from the membrane. A ribosome only binds to the RER once a specific protein-nucleic acid complex forms in the cytosol. This special complex forms when a free ribosome begins translating
of a protein destined for the secretory pathway
The first 5–30 amino acid
s polymerized encode a signal peptide
, a molecular message that is recognized and bound by a signal recognition particle
(SRP). Translation pauses and the ribosome complex binds to the RER translocon
where translation continues with the nascent
(new) protein forming into the RER lumen and/or membrane. The protein is processed in the ER lumen by an enzyme (a signal peptidase
), which removes the signal peptide. Ribosomes at this point may be released back into the cytosol; however, non-translating ribosomes are also known to stay associated with translocons.
The membrane of the rough endoplasmic reticulum forms large double-membrane sheets that are located near, and continuous with, the outer layer of the nuclear envelope
The double membrane sheets are stacked and connected through several right- or left-handed helical ramps, the "Terasaki ramps", giving rise to a structure resembling a multi-story car park
Although there is no continuous membrane between the endoplasmic reticulum and the Golgi apparatus
, membrane-bound transport vesicles
shuttle proteins between these two compartments. Vesicles are surrounded by coating proteins
called COPI and COPII. COPII
targets vesicles to the Golgi apparatus and COPI
marks them to be brought back to the rough endoplasmic reticulum. The rough endoplasmic reticulum works in concert with the Golgi complex
to target new proteins
to their proper destinations. The second method of transport out of the endoplasmic reticulum involves areas called membrane contact site
s, where the membranes of the endoplasmic reticulum and other organelles are held closely together, allowing the transfer of lipids and other small molecules.
The rough endoplasmic reticulum is key in multiple functions:
* Manufacture of lysosomal
enzymes with a mannose-6-phosphate
marker added in the ''cis''-Golgi network.
* Manufacture of secreted
proteins, either secreted constitutively with no tag or secreted in a regulatory manner involving clathrin
and paired basic amino acids in the signal peptide
* Integral membrane proteins
that stay embedded in the membrane as vesicles exit and bind to new membranes. Rab
proteins are key in targeting the membrane; SNAP
proteins are key in the fusion event.
* Initial glycosylation
as assembly continues. This is N-linked (O-linking occurs in the Golgi).
** N-linked glycosylation: If the protein is properly folded, oligosaccharyltransferase
recognizes the AA sequence N
(with the S/T residue phosphorylated) and adds a 14-sugar backbone (2-''N''-acetylglucosamine, 9-branching mannose
, and 3-glucose
at the end) to the side-chain nitrogen
Smooth endoplasmic reticulum
In most cells the smooth endoplasmic reticulum (abbreviated SER) is scarce. Instead there are areas where the ER is partly smooth and partly rough, this area is called the transitional ER. The transitional ER gets its name because it contains ER exit sites. These are areas where the transport vesicles that contain lipids and proteins made in the ER, detach from the ER and start moving to the Golgi apparatus
. Specialized cells can have a lot of smooth endoplasmic reticulum and in these cells the smooth ER has many functions.
It synthesizes lipids
, and steroids
. Cells which secrete these products, such as those in the testes
, and sebaceous gland
s have an abundance of smooth endoplasmic reticulum. It also carries out the metabolism of carbohydrates, detoxification of natural metabolism products and of alcohol and drugs, attachment of receptors on cell membrane proteins, and steroid metabolism
. In muscle cells, it regulates calcium ion
concentration. Smooth endoplasmic reticulum is found in a variety of cell types (both animal and plant), and it serves different functions in each. The smooth endoplasmic reticulum also contains the enzyme glucose-6-phosphatase
, which converts glucose-6-phosphate
to glucose, a step in gluconeogenesis
. It is connected to the nuclear envelope
and consists of tubules that are located near the cell periphery. These tubes sometimes branch forming a network that is reticular in appearance.
In some cells, there are dilated areas like the sacs of rough endoplasmic reticulum. The network of smooth endoplasmic reticulum allows for an increased surface area to be devoted to the action or storage of key enzymes and the products of these enzymes.
The sarcoplasmic reticulum (SR), from the Greek σάρξ ''sarx'' ("flesh"), is smooth ER found in myocytes
. The only structural difference between this organelle and the smooth endoplasmic reticulum is the medley of proteins they have, both bound to their membranes and drifting within the confines of their lumens. This fundamental difference is indicative of their functions: The endoplasmic reticulum synthesizes molecules, while the sarcoplasmic reticulum stores calcium ions and pumps them out into the sarcoplasm when the muscle fiber is stimulated.
After their release from the sarcoplasmic reticulum, calcium ions interact with contractile proteins that utilize ATP to shorten the muscle fiber. The sarcoplasmic reticulum plays a major role in excitation-contraction coupling
The endoplasmic reticulum serves many general functions, including the folding of protein molecules in sacs called cisterna
e and the transport of synthesized proteins in vesicles
to the Golgi apparatus
. Correct folding of newly made proteins is made possible by several endoplasmic reticulum chaperone
proteins, including protein disulfide isomerase
(PDI), ERp29, the Hsp70
family member BiP/Grp78
, and the peptidylpropyl isomerase family. Only properly folded proteins are transported from the rough ER to the Golgi apparatus – unfolded proteins cause an unfolded protein response
as a stress response in the ER. Disturbances in redox
regulation, calcium regulation, glucose deprivation, and viral infection or the over-expression of proteins
can lead to endoplasmic reticulum stress response
(ER stress), a state in which the folding of proteins slows, leading to an increase in unfolded proteins
. This stress is emerging as a potential cause of damage in hypoxia/ischemia, insulin resistance, and other disorders.
Secretory proteins, mostly glycoproteins
, are moved across the endoplasmic reticulum membrane. Proteins that are transported by the endoplasmic reticulum throughout the cell are marked with an address tag called a signal sequence
. The N-terminus (one end) of a polypeptide
chain (i.e., a protein) contains a few amino acid
s that work as an address tag, which are removed when the polypeptide reaches its destination. Nascent peptides reach the ER via the translocon
, a membrane-embedded multiprotein complex. Proteins that are destined for places outside the endoplasmic reticulum are packed into transport vesicle
s and moved along the cytoskeleton
toward their destination. In human fibroblasts, the ER is always co-distributed with microtubules and the depolymerisation of the latter cause its co-aggregation with mitochondria, which are also associated with the ER.
The endoplasmic reticulum is also part of a protein sorting pathway. It is, in essence, the transportation system of the eukaryotic cell. The majority of its resident proteins are retained within it through a retention motif
. This motif is composed of four amino acids at the end of the protein sequence. The most common retention sequences are KDEL
for lumen located proteins and KKXX
for transmembrane protein. However, variations of KDEL and KKXX do occur, and other sequences can also give rise to endoplasmic reticulum retention. It is not known whether such variation can lead to sub-ER localizations. There are three KDEL (1
) receptors in mammalian cells, and they have a very high degree of sequence identity. The functional differences between these receptors remain to be established.
Bioenergetics regulation of ER ATP supply by a CaATiER mechanism
The endoplasmic reticulum does not harbor an ATP-regeneration machinery, and therefore requires ATP import from mitochondria. The imported ATP is vital for the ER to carry out its house keeping cellular functions, such as for protein folding and trafficking.
The ER ATP transporter, SLC35B1/AXER, was recently cloned and characterized, and the mitochondria supply ATP to the ER through a ''Ca2+
-antagonized transport into the ER'' (''CaATiER'') mechanism. The ''CaATiER'' mechanism shows sensitivity to cytosolic Ca2+
ranging from high nM to low μM range, with the Ca2+
-sensing element yet to be identified and validated.
Abnormalities in XBP1
lead to a heightened endoplasmic reticulum stress response
and subsequently causes a higher susceptibility for inflammatory processes that may even contribute to Alzheimer's disease
In the colon
, XBP1 anomalies have been linked to the inflammatory bowel diseases including Crohn's disease
The unfolded protein response
(UPR) is a cellular stress response
related to the endoplasmic reticulum. The UPR is activated in response to an accumulation of unfolded or misfolded protein
s in the lumen
of the endoplasmic reticulum. The UPR functions to restore normal function of the cell by halting protein translation
, degrading misfolded proteins, and activating the signaling pathways that lead to increasing the production of molecular chaperones
involved in protein folding
. Sustained overactivation of the UPR has been implicated in prion
diseases as well as several other neurodegenerative diseases
and the inhibition of the UPR could become a treatment for those diseases.
External links Endoplasmic ReticulumLipid and protein composition of Endoplasmic reticulum
in OPM database
Animations of the various cell functions referenced here