Differentiated cells have evolved mechanisms to adapt the functions of the late secretory pathway to the specific needs of the organism. Reporting in this issue of Developmental Cell, Polishchuk et al. (2014) demonstrate that hepatocytes utilize a unique exocytic aspect of the late endosomal/lysosomal compartment to maintain organismal copper homeostasis

Gitlin, Jonathan D.

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Developmental Cell
PreviewsCopper Homeostasis: Specialized Functions
of the Late Secretory PathwayJonathan D. Gitlin1,*
1Marine Biological Laboratory, Woods Hole, MA 02543, USA
*Correspondence: jgitlin@mbl.edu
http://dx.doi.org/10.1016/j.devcel.2014.06.002
Differentiated cells have evolved mechanisms to adapt the functions of the late secretory pathway to the
specific needs of the organism. Reporting in this issue ofDevelopmental Cell, Polishchuk et al. (2014) demon-
strate that hepatocytes utilize a unique exocytic aspect of the late endosomal/lysosomal compartment to
maintain organismal copper homeostasis.Although originally characterized as a
specialized digestive compartment of
the cell, lysosomes are now recognized
to have critical roles in membrane traf-
ficking, endocytosis, and intracellular
protein sorting. As might be anticipated
from these essential functions in cellular
physiology, these organelles are also
involved in the pathophysiology of
numerous metabolic and storage dis-
eases. Within differentiated cell types,
lysosomes assume unique roles specific
to the functions of organs or tissues, for
example pigment formation in melano-
somes (Appelqvist et al., 2013). Within
the late secretory pathway, lysosomes
participate in highly specialized functions
such as bone resorption and extracellular
signaling through a process of exocytosis
that involves fusion with the plasma
membrane. In this issue ofDevelopmental
Cell, Polishchuk and colleagues (2014)
show that hepatocytes utilize this unique
exocytic aspect of the late endosomal/
lysosomal compartment to maintain
organismal copper homeostasis.
Copper is an essential transition
element that plays a fundamental role as
a cofactor in a select number of enzy-
matic pathways essential for cellular
respiration, iron homeostasis, pigment
formation, neurotransmitter production,
peptide biogenesis, connective tissue
biosynthesis, and antioxidant defense. In
mammals, copper homeostasis is main-
tained entirely by gastrointestinal ab-
sorption and biliary excretion. Absorbed
copper is efficiently removed from the cir-
culation by the liver, which regulates the
storage and excretion of this metal. Biliary
excretion is the predominant mechanism
determining copper balance, and the
amount of copper appearing in bile isdirectly proportional to the size of the
hepatic copper pool. Hepatocytes are
therefore the primary site of copper ho-
meostasis as these polarized epithelial
cells discern copper status and regulate
copper excretion into the bile, depending
on the intracellular concentration of this
metal (Madsen and Gitlin, 2007).
The molecular mechanisms by which
the hepatocyte determines copper home-
ostasis were clarified with the eluci-
dation of the genetic defect in Wilson
disease, a disorder of excess copper
accumulation resulting from loss-of-
function mutations in the copper-trans-
porting ATPase Atp7b (Gitlin, 2003).
Atp7b is localized to the trans-Golgi
network of the hepatocyte, and, as
the copper concentration increases, this
protein moves from the trans-Golgi
network to a cytoplasmic vesicular com-
partment, which until now has remained
uncharacterized. Following sequestration
of copper into this compartment by
Atp7b, the concomitant decrease in cyto-
solic copper concentration initiates the
return of this ATPase to the trans-Golgi
network while the copper is discharged
at the canalicular (apical) membrane.
This novel posttranslational mechanism
ensures that excess cytosolic copper
will be excreted rapidly into the bile (Gitlin,
2003).
In this current study, Polishchuk et al.
(2014) demonstrate that the vesicular
compartment containing Atp7b resides
within the late endosome/lysosome
pathway. Specifically, the authors demon-
strate that exposure of hepatocytes to
increasing copper concentrations results
in direct trafficking of Atp7b from the
trans-Golgi network to a specific subset
of organelles with molecular characteris-Developmental Celltics of lysosomes, including LAMP1 and
CD63. Increasing the intracellular copper
concentration resulted in apical (canalic-
ular) localization of Atp7b in a polarized
hepatocyte cell line with concomitant
lysosomal exocytosis, suggesting that
this exocytic process may serve as the
primary mechanism for copper excretion
into the bile. Consistent with this concept,
activation of lysosomal exocytosis with
the transcriptional regulator TFEB re-
sulted in increased movement of Atp7b
to the apical surface, whereas inhibition
of exocytosis with mucolipin-1 decreased
this trafficking. In these experiments,
the authors measured lysosomal exocy-
tosis utilizing a copper-sensitive dye
that detects intracellular concentration
of exchangeable copper. Furthermore,
abrogating Atp7b expression in this polar-
ized hepatocyte cell line revealed a direct
role for Atp7b in copper import into lyso-
somes and in the apical exocytosis of cop-
per. Additional studies suggest that the
direct interaction between Atp7b and the
p62 subunit of dynactin, a multi-subunit
complex mediating dynein binding and
vesicle transport along microtubules,
mayaccount for theAtp7b-mediated lyso-
somal apical trafficking.
Taken together, these new studies pro-
vide clear evidence for a direct role of
the late endosomal/lysosomal pathway
in mediating copper homeostasis through
exocytosis at the biliary canalicular
membrane. Importantly, these observa-
tions must now be placed in the context
of recent genetic (Ishizaki et al., 2010;
Martinelli and Dionisi-Vici, 2014) and cell
biological (Holloway et al., 2013; Hirst
et al., 2012) studies that reveal a direct
role for clathrin-coated vesicles (CCV)
and the adaptor protein 1 (AP-1) complex29, June 23, 2014 ª2014 Elsevier Inc. 631
Developmental Cell
Previewsin the endosomal trafficking and retrieval
of Atp7b to the trans-Golgi network.
Intriguingly, increasing copper concentra-
tions disrupt this AP-1 CCV interaction,
suggesting additional molecular mecha-
nisms whereby Atp7b maintains intracel-
lular copper homeostasis. Further work
should now focus on linking these obser-
vations to develop a clearer picture of
how these copper-containing compart-
ments are maintained in the late secretory
pathway, what the precise molecular
nature is of the copper within the com-
partments, and what role if any Atp7b
plays in this process directly at the site
of biliary excretion. Although the authors
suggest that there may be differences in
excretion mechanisms dependent upon
the hepatic copper content, physiolog-
ical data suggest that this process is
most likely a continuum that is constantly
adapting to changes in intracellular cop-
per to maintain physiologic organismal
homeostasis.632 Developmental Cell 29, June 23, 2014 ª2While providing new insight into the
cellular pathways affected in Wilson dis-
ease, the true importance of this work is
in the broad recognition that a unique
aspect of late endosome/lysosome func-
tion can be adapted in a highly differenti-
atedcell to permit the regulation of homeo-
stasis of a specificmetal. This is consistent
with our evolving understanding of the
specialized roles of the late secretory
pathway and is unlikely to be the only
example of such a process in the liver, an
organ that is critical for the metabolism
and excretion of a myriad of metabolites
andxenobiotics.Assuch, theobservations
of Polishchuk et al. (2014) suggest an
exciting new venue for investigation into
the role of the late secretory pathway in he-
patic specific cell biological processes and
the pathophysiology of disease; these ob-
servations also have important therapeutic
implications for understanding themecha-
nisms resulting in the stimulationof hepatic
lysosomal exocytosis.014 Elsevier Inc.REFERENCES
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Sheds Light on piRNA AmplificationJulie M. Claycomb1,*
1Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada
*Correspondence: julie.claycomb@utoronto.ca
http://dx.doi.org/10.1016/j.devcel.2014.06.009
Reporting in a recent study in Cell, Xiol and colleagues (2014) identify the conserved DEAD box helicase
Vasa as a platform for secondary Piwi-interacting RNA (piRNA) biogenesis in the insect nuage. This study
represents a substantial breakthrough in understanding the mechanism and location of piRNA amplification
by the ‘‘ping-pong’’ cycle.Small RNA pathways have long been
hailed as guardians of the genome and
are thought to carry out this role by re-
pressing deleterious transcripts. Perhaps
in no tissue is this activity more important
than in the gonad, which holds the poten-
tial to dictate the integrity of a species. In
animal gonads, the Piwi-interacting RNA
(piRNA) pathway is the major small RNA-
mediated protector of the genome. This
pathway utilizes a particular subset of
Argonaute effectors, the Piwi clade, that
are guided by a diverse repertoire of smallRNA sequences, the piRNAs (24–30 nt),
to silence transposable elements (TEs).
piRNA regulation of TEs occurs at both
the transcriptional and posttranscriptional
levels and aims to prevent devastating
effects due to TE mobilization, such as
mutations in protein coding genes and
double-strand breaks that activate the
DNA damage response and lead to ste-
rility (for review, see Luteijn and Ketting,
2013). While the importance of the piRNA
pathway is readily evident in animals, the
mechanisms by which piRNAs are pro-duced have remained relatively elusive,
especially in comparison to other types
of small RNAs, such as microRNAs or
small interfering RNAs. In a landmark
study published in Cell, Xiol et al. (2014)
close key gaps in our understanding of
where and how piRNAs are generated
by making clever use of a mutation that
fortuitously decreases the in vivo dy-
namics of Vasa helicase, a key factor in
the piRNA pathway.
piRNA biogenesis begins in the nu-
cleus with the transcription of clusters


Copper Homeostasis: Specialized Functions of the Late Secretory Pathway 

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Copper Homeostasis: Specialized Functions of the Late Secretory Pathway

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