Peroxisomal localization of the proopiomelanocortin-derived peptides beta-lipotropin and beta-endorphin.
The peptide hormones ACTH, MSHs, β-lipotropin (β-LPH), and β-endorphin are all derived from the precursor molecule proopiomelanocortin (POMC). Using confocal laser microscopy and immunoelectron microscopy in human pituitary gland, we demonstrate a peroxisomal localization of β-endorphin and β-LPH in cells expressing the peroxisomal ATP-binding cassette-transporter adrenoleukodystrophy protein (ALDP). The peroxisomal localization of β-LPH and β-endorphin was not restricted to the pituitary gland but was additionally found in other human tissues that express high levels of ALDP, such as dorsal root ganglia, adrenal cortex, distal tubules of kidney, and skin. In contrast to the peptide hormones β-LPH and β-endorphin, which are derived from the C terminus of POMC, the N-terminal peptides ACTH, α-MSH, and γ-MSH were never detected in peroxisomes. This novel peroxisomal localization of β-endorphin and β-LPH in ALDP-positive cells was confirmed by costaining with ALDP and the peroxisomal marker catalase. Moreover, peroxisomal sorting of β-LPH could be modeled in HeLa cells by ectopic expression of a POMC variant, modified to allow cleavage and release of β-LPH within the secretory pathway. Although β-LPH and β-endorphin were only associated with peroxisomes in cells that normally express ALDP, the transporter activity of ALDP is not necessary for the peroxisomal localization, as demonstrated in tissues of X-linked adrenoleukodystrophy patients lacking functional ALDP. It remains to be elucidated whether and how the peroxisomal localization of POMC-derived hormones has a role in the endocrine dysfunction of peroxisomal disease.
Höftberger
Romana
R
Institute of Neurology, Center for Brain Research, Medical University of Vienna, and Department of Neurology, SMZ-Ost Danube Hospital, AKH 4J, Währinger Gürtel 18-20, P.O. Box 48, A-1097 Vienna, Austria. romana.hoeftberger@meduniwien.ac.at
Kunze
Markus
M
Voigtländer
Till
T
Unterberger
Ursula
U
Regelsberger
Günther
G
Bauer
Jan
J
Aboul-Enein
Fahmy
F
Garzuly
Ferenc
F
Forss-Petter
Sonja
S
Bernheimer
Hanno
H
Berger
Johannes
J
Budka
Herbert
H
D000074063:ATP Binding Cassette Transporter, Subfamily D, Member 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D018929:Cell Culture Techniques; D006367:HeLa Cells; D006801:Humans; D009928:Organ Specificity / Q000235:genetics; D020675:Peroxisomes / Q000378:metabolism*; D010902:Pituitary Gland / Q000378:metabolism; D011333:Pro-Opiomelanocortin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport; D014018:Tissue Distribution; D001615:beta-Endorphin / Q000235:genetics / Q000378:metabolism*; D008083:beta-Lipotropin / Q000235:genetics / Q000378:metabolism*
C115572:ABCD1 protein, human; D000074063:ATP Binding Cassette Transporter, Subfamily D, Member 1; D018528:ATP-Binding Cassette Transporters; D001615:beta-Endorphin; D011333:Pro-Opiomelanocortin; D008083:beta-Lipotropin