A Primer on Keratins
What
they are:
Keratins
are the most abundant proteins in epithelial cells, and
are encoded by two groups of genes, type I and type II,
which are distinct at the level of genomic structure and
nucleotide sequence. There are >20 type I and > 15 type
II keratin genes, and each are clustered within separate
loci in the mouse and human genomes. Type II keratin proteins
are comprised of K1-K8 in soft epithelia and Hb1-Hb8 in
hard epithelia (hair, nail, and parts of the tongue epithelium),
whereas type I keratins are comprised of K9-K20 in soft
epithelia and Ha1-Ha10 in hard epithelia. A comparison of
keratin proteins expressed in human soft epithelia can be
found here. Keratins are the epithelial-specific
members of the superfamily of intermediate
filament (IF) proteins, and as such they form 10
nm-wide cytoskeletal filaments. All epithelial cells
coordinately regulate the expression of at least one type
I and one type II gene, reflecting the requirement for both
types of proteins in a 1:1 molar ratio to sustain productive
IF assembly. Whereas any combination of type I and type
II keratins can produce a fibrous polymer when co-polymerized
in vitro, many type I and type II keratin genes are in fact
regulated in a pairwise, epithelial tissue type-, and differentiation-specific
manner, giving rise to "patterns" that have been and continue
to be useful to study epithelial growth and differentiation.
Relationship to epithelial
differentiation:
Beyond
the vast number of keratin sequences and their fairly non-descript
nomenclature, there is an apparent logic in the regulation
of keratin genes that "facilitates" the study of differentiation
in epithelial cells and tissues. In all complex epithelia,
for instance, progenitor cells transcribe a common set of
keratin genes that consists of the type II K5"
and the type I K14
genes (along with variable amounts of K15
or K19, two additional
type I keratins). Post-mitotic, suprabasal cells in these
epithelia transcribe other pairs of keratin genes, the identity
of which depends on the program of terminal differentiation
being executed. Thus the K1
and K10 pair is characteristic
of the post-mitotic compartment of cornifying epithelia
(e.g., epidermis), the K4-K13 pair is expressed in several
"wet" epithelia (e.g. oral mucosa, tongue, esophagus), and
the K3-K12 pair is found in the cornea. The tightly regulated
expression of these genes in complex epithelia, and the
conservation of the sequences involved and their regulation
across species, suggest the existence of a direct link between
keratin gene expression and epithelial cell function. Follow
this link
for a schematic depicting the expression of keratin genes
in human trunk epidermis.
Organization of Keratin
Filaments: In most epithelial cells the keratin
filament network spans the entire cytoplasm, from the
surface of the nucleus to the cell periphery where it interacts
with cell matrix (hemidesmosomes) and cell-cell (desmosomes)
adhesion complexes. As for other cytoskeletal arrays, the
spatial organization of IFs in the cytoplasm is a crucial
determinant of their function (see below). However, very
few cross-bridging proteins are specific for keratin IFs
- most IF-associated proteins known to exert a structural
role act to tether IFs to other major cytokeletal elements,
such as F-actin, microtubules, or adhesion complexes. In
addition, keratin IFs are endowed with the ability to participate
in their own organization. For additional information about
this issue condult the following review article
Function and role in disease:
The general function of keratin IF networks is to endow
epithelial cells with the mechanical resilience they need
to sustain incident mechanical stress. The evidence for
this is by now definitive, and comes from two main sources:
mouse strains harboring null mutations for specific keratin
genes, and patients with keratin-based inherited bullous
diseases. Follow this link
for an example of blistering epithelial disease arising
as a result of defective or absent keratin filament networks.
Why so many genes?
Given this simple function, what does keratin sequence diversity
means ? It has recently been reported that neither K18
nor K16 can
fully complement the skin blistering and postnatal death
phenotypes associated with a null mutation in the mouse
K14 gene. This directly demonstrates that these keratin
proteins are not interchangeable in vivo. Moreover, other
researchers have proposed, based on transgenic mouse studies,
that the simple epithelial keratins K8 and K18 protect the
liver hepatocyte against not only mechanical, but chemical
stresses as well. Whether sequence diversification makes
possible the performance of other function(s), or simply
reflects a specialization to best fulfill the scaffolding
needs of various types of epithelial cell types, awaits
further study.
