A1 Refereed original research article in a scientific journal
p62/SQSTM1 regulates cellular oxygen sensing by attenuating PHD3 activity through aggregate sequestration and enhanced degradation
Authors: Rantanen K, Pursiheimo JP, Hogel H, Miikkulainen P, Sundstrom J, Jaakkola PM
Publisher: COMPANY OF BIOLOGISTS LTD
Publication year: 2013
Journal: Journal of Cell Science
Journal name in source: JOURNAL OF CELL SCIENCE
Journal acronym: J CELL SCI
Number in series: 5
Volume: 126
Issue: 5
First page : 1144
Last page: 1154
Number of pages: 11
ISSN: 0021-9533
DOI: https://doi.org/10.1242/jcs.115667(external)
Web address : http://api.elsevier.com/content/abstract/scopus_id:84877877932(external)
The hypoxia-inducible factor (HIF) prolyl hydroxylase PHD3 regulates cellular responses to hypoxia. In normoxia the expression of PHD3 is low and it occurs in cytosolic aggregates. SQSTM1/p62 (p62) recruits proteins into cytosolic aggregates, regulates metabolism and protein degradation and is downregulated by hypoxia. Here we show that p62 determines the localization, expression and activity of PHD3. In normoxia PHD3 interacted with p62 in cytosolic aggregates, and p62 was required for PHD3 aggregation that was lost upon transfer to hypoxia, allowing PHD3 to be expressed evenly throughout the cell. In line with this, p62 enhanced the normoxic degradation of PHD3. Depletion of p62 in normoxia led to elevated PHD3 levels, whereas forced p62 expression in hypoxia downregulated PHD3. The loss of p62 resulted in enhanced interaction of PHD3 with HIF-alpha and reduced HIF-alpha levels. The data demonstrate p62 is a critical regulator of the hypoxia response and PHD3 activity, by inducing PHD3 aggregation and degradation under normoxia.
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