LIV-1 ZIP ectodomain shedding in prion-infected mice resembles cellular response to transition metal starvation.
We recently documented the co-purification of members of the LIV-1 subfamily of ZIP (Zrt-, Irt-like Protein) zinc transporters (LZTs) with the cellular prion protein (PrP(C)) and, subsequently, established that the prion gene family descended from an ancestral LZT gene. Here, we begin to address whether the study of LZTs can shed light on the biology of prion proteins in health and disease. Starting from an observation of an abnormal LZT immunoreactive band in prion-infected mice, subsequent cell biological analyses uncovered a surprisingly coordinated biology of ZIP10 (an LZT member) and prion proteins that involves alterations to N-glycosylation and endoproteolysis in response to manipulations to the extracellular divalent cation milieu. Starving cells of manganese or zinc, but not copper, causes shedding of the N1 fragment of PrP(C) and of the ectodomain of ZIP10. For ZIP10, this posttranslational biology is influenced by an interaction between its PrP-like ectodomain and a conserved metal coordination site within its C-terminal multi-spanning transmembrane domain. The transition metal starvation-induced cleavage of ZIP10 can be differentiated by an immature N-glycosylation signature from a constitutive cleavage targeting the same site. Data from this work provide a first glimpse into a hitherto neglected molecular biology that ties PrP to its LZT cousins and suggest that manganese or zinc starvation may contribute to the etiology of prion disease in mice.
Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON, Canada M5S 3H2.|Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada M5S 1A8.
Sepehr
S
Ehsani
Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON, Canada M5S 3H2.|Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada M5S 1A8.
Ashkan
A
Salehzadeh
Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON, Canada M5S 3H2.
Hairu
H
Huo
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada M5S 1A8.
William
W
Reginold
Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON, Canada M5S 3H2.
Cosmin L
CL
Pocanschi
Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON, Canada M5S 3H2.|Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada M5S 1A8.
Hezhen
H
Ren
Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON, Canada M5S 3H2.
Hansen
H
Wang
Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON, Canada M5S 3H2.
Kelvin
K
So
Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON, Canada M5S 3H2.
Christine
C
Sato
Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON, Canada M5S 3H2.|Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada M5S 1A8.
Mohadeseh
M
Mehrabian
Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON, Canada M5S 3H2.
Robert
R
Strome
Program in Cell Biology, Hospital for Sick Children, Toronto, ON, Canada M5G 1X8.
William S
WS
Trimble
Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON, Canada M5S 3H2.|Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada M5S 1A8.
Lili-Naz
LN
Hazrati
Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON, Canada M5S 3H2.|Department of Medicine, University of Toronto, Toronto, ON, Canada M5G 2C4.
Ekaterina
E
Rogaeva
Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, AB, Canada T6G 2M8.
David
D
Westaway
McLaughlin Research Institute, Great Falls, MT 59405, USA.
George A
GA
Carlson
Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON, Canada M5S 3H2.|Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada M5S 1A8.
Gerold
G
Schmitt-Ulms
D000595:Amino Acid Sequence; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D027682:Cation Transport Proteins / Q000378:metabolism*; D002413:Cations, Divalent / Q000378:metabolism; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D006031:Glycosylation; D008565:Membrane Proteins / Q000378:metabolism; D008670:Metals / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D017096:Prion Diseases / Q000378:metabolism; D011328:Prions / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D059748:Proteolysis; D028561:Transition Elements / Q000378:metabolism*; D015032:Zinc / Q000378:metabolism
D002352:Carrier Proteins; D027682:Cation Transport Proteins; D002413:Cations, Divalent; D008565:Membrane Proteins; D008670:Metals; D011328:Prions; D028561:Transition Elements; C557566:ZIP10 protein, mouse; C017800:zinc-binding protein; D015032:Zinc