Endoplasmic Reticulum and the Unfolded Protein Response: Dynamics and Metabolic Integration - International Review of Cell and Molecular Biology - page 223

Phosphatidylinositol is synthesized in the ER by phosphatidylinositol
synthase, and derivatives with different levels of phosphorylation are formed in
the ER and play an important role in signaling and vesicle trafficking ( Fagone
and Jackowski, 2009 ).
De novo synthesis of sphingolipids and ceramides begins in the cyto-
plasm. Then, intermediates are generated in the ER and the process con-
cludes in the Golgi apparatus and nucleus. The coordinated action of serine
palmitoyltransferase, 3-ketodihydrosphingosine reductase and dihydroc-
eramide synthase in the ER, convert serine and palmitoyl-CoA into cell
membrane components ( Gault et al., 2010 ).
Cholesterol synthesized at the ER is important for cell function due
to this molecule's structural role in membranes and as a precursor of vari-
ous steroid hormones and bile salts. The 3-hydroxy-3-methyl-glutaryl CoA
reductase, found in the membrane of the ER, participates in the first phase
of cholesterol synthesis, which leads to the combination of three molecules
of acetyl-CoA to form mevalonate. Mevalonate is then transformed into
3-isopentyl pyrophosphate. The condensation of six molecules of isopen-
tyl pyrophosphate gives rise to squalene, owing to the action of a series
of transferases and squalene synthase. Squalene is then cyclized by lanos-
terol cyclase, yielding lanosterol. After 19 reactions of bond reduction and
methyl-group elimination, catalyzed by various enzymes, cholesterol is ulti-
mately generated. Steroid hormones and bile acids are formed subsequently
through the action of other pathways ( Jo and Debose-Boyd, 2010 ; Maxfield
and van Meer, 2010 ).
2.3. Endoplasmic Reticulum Dynamics
The tubular structure of the ER is highly dynamic and undergoes con-
stant morphological remodeling. The cytoskeleton formed by microtubules
(MTs), microfilaments and intermediate filaments plays a crucial role in
the organization and structure of the ER. Treatment with depolymeriz-
ing agents reversibly and dramatically alters ER shape, causing slow retrac-
tion from the periphery to the center of the cell. MT and ER are highly
interdependent structures. While the distribution of ER and MT are not
identical, ER elongation and MT polymerization are tightly connected.
The maintenance of the ER network requires the MT system ( Terasaki
et al., 1986 ). For example, the RER-specific membrane protein, CLIMP-
63, mediates the interaction between this organelle and MTs through its
cytosolic domain, and is responsible for the restraining mobility of the TC
( Nikonov et al., 2007 ).