(Philadelphia, PA) – Researchers at the
University of Pennsylvania School of Medicine have
discovered how a protein called Pmel17 is sorted by pigment cells
in the skin and eye to make a fiber matrix that eventually sequesters
melanin, the dark pigment found in skin, hair, and eyes. Understanding
the molecular steps prior to fiber formation – and when this
process goes awry – may lead to a better understanding of
melanoma and Alzheimer’s disease. Pmel17 is a major target
within the immune system in current anti-melanoma immunotherapies.
Michael S. Marks, PhD, Associate Professor of Pathology
and Laboratory Medicine, and colleagues published their findings
in the March issue of Developmental Cell.
Marks studies protein sorting – determining how proteins are
delivered to the correct organelle, or subcompartments, within the
cell. He investigates this basic process in pigment cells, particularly
sorting to the melanin storage compartment called the melanosome.
Melanin is normally stored by the cell in melanosomes because its
build-up outside the melanosome can lead to cell death.
the pigment-producing cell, called the melanocyte, melanin is laid
down on a fibrous matrix made from Pmel17. Other work from the Marks
lab and collaborators showed that the structure of Pmel17 is similar
to amyloid protein, one of the hallmarks of Alzheimer’s disease
plaques. Using mouse and human melanoma cells, the Marks lab also
studies melanocytes for pathological conditions associated with
mutations along the protein-sorting process.
“There’s no evidence that Pmel17 per se will initiate
pathological cellular structures, but recent research from our lab
shows that if we look at the structure of the fibers made up of
Pmel17, it has all the biophysical properties of amyloid,”
explains Marks. “Pmel17 is functioning in a physiological
capacity the same way that amyloid functions in a pathological capacity.”
Before the fibers are laid down, the researchers found in the Developmental
Cell study that Pmel17 passes through a series of compartments
called endosomes, much the way proteins that are tagged for degradation
do. They determined that this process also happens in non-pigment
cells. This discovery indicates that sorting is not a melanocyte-specific
process; the sorting phenomenon is a general one.
Other researchers have found that the Alzheimer’s precursor
protein, the prion protein (responsible for Jakob-Creuztfeldt’s
Disease, Mad Cow disease, and Kuru), and the precursors for several
familial amyloid diseases all pass through one type of endosome.
“This may be a general property of a class of amyloids –
and the fact that the process happens in non-pigment cells means
that it can also happen in neurons or epithelial cells where these
amyloids cause problems,” says Marks.
Pmel17 and other proteins of melanocytes are well-known tumor antigens
in melanoma patients. “What’s unique about these proteins,
as opposed to other tumor antigens, is that there’s good evidence
in melanoma patients that – via Pmel17 – you can stimulate
helper T cells, whose antigens are also processed within the cell
by protein- sorting mechanisms,” says Marks.
Exosomes are the special membranes with which the antigens associate
in the protein-sorting process and are derived from endosome membranes.
Hence, if the antigens get to the right endosome, they will be incorporated
on exosomes. Once released outside the cell, the exosomes themselves
get targeted to dendritic cells. Then exosomes ferry Pmel17 and
other melanoma antigens from the melanoma tumor cell to the dendritic
“Exosomes are a very hot topic now in cancer immunotherapy
because dendritic cells are good at taking them up, processing the
associated antigens, and presenting them to helper T cells, which
then rally the immune system to fight the tumor.”
Marks says that understanding how and why the sorting process is
required for Pmel17 fiber formation will likely provide researchers
with the chance to interfere with this process, and may thus provide
some therapeutic or preventative treatments for diseases like Alzheimer’s
and the prion diseases.
“We’ve also shown a new way of targeting proteins to
exosomes,” says Marks. “If we learn more about how this
process works, we may be able to better manipulate tumor antigen
access to dendritic cells and perhaps their ability to stimulate
Study co-authors are Alexander C. Theos, Steven T. Truschel, Dawn
C. Harper, Joanne F. Berson, and Penelope C. Thomas, all from Penn,
as well as Ilse Hurbain and Graça Raposo from the Institut
Curie in Paris. This research was funded in part by the National
Eye Institute, the National Institute of Arthritis, Musculoskeletal
and Skin Diseases, the National Cancer Institute, and an American
Cancer Society Fellowship.
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