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Kortvely, E.* ; Hauck, S.M. ; Behler, J. ; Ho, N.* ; Ueffing, M.*

The unconventional secretion of ARMS2.

Hum. Mol. Genet. 25, 3143-3151 (2016)
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Age-related maculopathy susceptibility 2 (ARMS2) is a small (11 kDa), primate-specific protein found in the extracellular matrix of the choroid layer in the eye. Variants in the corresponding genetic locus are highly associated with age-related macular degeneration (AMD), a leading cause of blindness in the elderly. So far, the physiological function of ARMS2 has remained enigmatic. It has been demonstrated that ARMS2 is a genuine secreted protein devoid of an N-terminal leader sequence, yet the mechanism how it exits the cells and enters the choroidal matrix is not understood.Here we show that ARMS2 efficiently recruits lectin chaperones from the cytosol and colocalizes with calnexin-positive and PDI-negative vesicle-like structures. Site-directed mutagenesis revealed critical elements for this interaction. Mutant forms proving unable to interact with the calnexin/calreticulin system failed secretion. On the other hand, blocking the ER to Golgi transport with BFA had no effect on ARMS2 secretion.As we found ARMS2 colocalizing with GRASP65, a marker for unconventional protein secretion, autophagic factors are likely to be key in its export. Interleukin-1ß (IL-1ß) is the most established example of secretory autophagy. Co-expression experiments, however, suggest that the transport of ARMS2 is different from that of IL-1ß. In conclusion, in this work we show that ARMS2 is externalized via an unconventional pathway bypassing Golgi. Its intracellular separation from the classical secretion pathway suggests that the maturation of the protein requires a specific biochemical niche and/or may be needed to impede the premature formation of unwanted protein-protein interactions.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Endoplasmic-reticulum; Macular Degeneration; Protein Secretion; Containing Exosomes; Inclusion-bodies; Messenger-rna; Expression; Membrane; Loc387715; Resident
ISSN (print) / ISBN 0964-6906
e-ISSN 1460-2083
Quellenangaben Volume: 25, Issue: 15, Pages: 3143-3151 Article Number: , Supplement: ,
Publisher Oxford University Press
Publishing Place Oxford
Reviewing status Peer reviewed