Limits...
Hypoxia signaling pathways: modulators of oxygen-related organelles.

Schönenberger MJ, Kovacs WJ - Front Cell Dev Biol (2015)

Bottom Line: We discuss our recent findings that establish HIF-2α as a negative regulator of peroxisome abundance and suggest a mechanism by which cells attune peroxisomal function with O2 availability.HIF-2α activation augments peroxisome turnover by pexophagy and thereby changes lipid composition reminiscent of peroxisomal disorders.We discuss potential mechanisms by which HIF-2α might trigger pexophagy and place special emphasis on the potential pathological implications of HIF-2α-mediated pexophagy for human health.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, Institute of Molecular Health Sciences ETH Zurich, Zurich, Switzerland.

ABSTRACT
Oxygen (O2) is an essential substrate in cellular metabolism, bioenergetics, and signaling and as such linked to the survival and normal function of all metazoans. Low O2 tension (hypoxia) is a fundamental feature of physiological processes as well as pathophysiological conditions such as cancer and ischemic diseases. Central to the molecular mechanisms underlying O2 homeostasis are the hypoxia-inducible factors-1 and -2 alpha (HIF-1α and EPAS1/HIF-2α) that function as master regulators of the adaptive response to hypoxia. HIF-induced genes promote characteristic tumor behaviors, including angiogenesis and metabolic reprogramming. The aim of this review is to critically explore current knowledge of how HIF-α signaling regulates the abundance and function of major O2-consuming organelles. Abundant evidence suggests key roles for HIF-1α in the regulation of mitochondrial homeostasis. An essential adaptation to sustained hypoxia is repression of mitochondrial respiration and induction of glycolysis. HIF-1α activates several genes that trigger mitophagy and represses regulators of mitochondrial biogenesis. Several lines of evidence point to a strong relationship between hypoxia, the accumulation of misfolded proteins in the endoplasmic reticulum, and activation of the unfolded protein response. Surprisingly, although peroxisomes depend highly on molecular O2 for their function, there has been no evidence linking HIF signaling to peroxisomes. We discuss our recent findings that establish HIF-2α as a negative regulator of peroxisome abundance and suggest a mechanism by which cells attune peroxisomal function with O2 availability. HIF-2α activation augments peroxisome turnover by pexophagy and thereby changes lipid composition reminiscent of peroxisomal disorders. We discuss potential mechanisms by which HIF-2α might trigger pexophagy and place special emphasis on the potential pathological implications of HIF-2α-mediated pexophagy for human health.

No MeSH data available.


Related in: MedlinePlus

Three alternative models illustrating how HIF-2α might trigger pexophagy. (A) HIF-2α might induce an E3 ubiquitin ligase that ubiquitinates a PMP that enhances the recruitment of the autophagy receptor NBR1 to the peroxisome surface. Accumulation of NBR1 on peroxisomes likely recruits SQSTM1, which was suggested to act as pexophagy co-receptor, and subsequently leads to clustering of peroxisomes via oligomerization of receptor-bound organelles. Accumulation of a critical mass of autophagy receptors might prime phagophore assembly at peroxisomes. (B) NBR1 could be recruited to peroxisomes independently of ubiquitin via its membrane-interacting amphipathic α-helical J domain. HIF-2α might induce or inhibit a kinase/phosphatase that leads to a change in the posttranslational modification of peroxisome-bound NBR1 and thereby triggers recruitment of the autophagic machinery. (C) HIF-2α-dependent activation of pexophagy might be a 2-step process and HIF-2α functions as master regulator that combines two layers of posttranslational modifications to trigger pexophagy. First, it induces an E3 ubiquitin ligase leading to an increased ubiquitination of PMP(s) and subsequent accumulation of NBR1 and SQSTM1 on peroxisomes. Second, HIF-2α activates or inhibits a kinase/phosphatase that leads to a change in the posttranslational modification of peroxisome-bound NBR1 and thereby enhances its binding affinity to a LC3 homolog that finally results in pexophagy. Modified from Schönenberger et al. (2015).
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4508581&req=5

Figure 6: Three alternative models illustrating how HIF-2α might trigger pexophagy. (A) HIF-2α might induce an E3 ubiquitin ligase that ubiquitinates a PMP that enhances the recruitment of the autophagy receptor NBR1 to the peroxisome surface. Accumulation of NBR1 on peroxisomes likely recruits SQSTM1, which was suggested to act as pexophagy co-receptor, and subsequently leads to clustering of peroxisomes via oligomerization of receptor-bound organelles. Accumulation of a critical mass of autophagy receptors might prime phagophore assembly at peroxisomes. (B) NBR1 could be recruited to peroxisomes independently of ubiquitin via its membrane-interacting amphipathic α-helical J domain. HIF-2α might induce or inhibit a kinase/phosphatase that leads to a change in the posttranslational modification of peroxisome-bound NBR1 and thereby triggers recruitment of the autophagic machinery. (C) HIF-2α-dependent activation of pexophagy might be a 2-step process and HIF-2α functions as master regulator that combines two layers of posttranslational modifications to trigger pexophagy. First, it induces an E3 ubiquitin ligase leading to an increased ubiquitination of PMP(s) and subsequent accumulation of NBR1 and SQSTM1 on peroxisomes. Second, HIF-2α activates or inhibits a kinase/phosphatase that leads to a change in the posttranslational modification of peroxisome-bound NBR1 and thereby enhances its binding affinity to a LC3 homolog that finally results in pexophagy. Modified from Schönenberger et al. (2015).

Mentions: Since HIF-2α is a transcription factor, the most likely possibility would be that HIF-2α induces the expression of an autophagy receptor and subsequent clustering of peroxisomes via oligomerization of receptor-bound organelles, however, neither Nbr1 nor Sqstm1 are HIF-2α target genes (Walter et al., 2014). Ubiquitination of cargo prone for selective autophagic degradation is the most prevalent autophagy-targeting signal in mammals, and most of the currently known autophagy receptors harbor both ubiquitin-binding domains and LIRs (Kirkin et al., 2009; Stolz et al., 2014). HIF-2α might induce an E3 ubiquitin ligase that mediates the ubiquitination of a PMP (Figure 6A). We propose that HIF-2α signaling increases in this manner NBR1 accumulation on peroxisomes, which in turn serves as a platform for the recruitment of SQSTM1 to achieve a critical mass of autophagy receptors on peroxisomes required for pexophagy (Schönenberger et al., 2015). This might concentrate sufficient ubiquitin-like modifiers (e.g., LC3 and GABARAPs) in close proximity to peroxisomes to prime phagophore assembly. The peroxisomal membrane harbors three E3 ligases (PEX2, PEX10, PEX12) that are essential for peroxisome biogenesis and involved in PEX5 receptor ubiquitination. Their transcriptional induction and concomitant increase of protein levels could increase their ubiquitination capability leading to enhanced ubiquitination of PMPs, but HIF-2α does not induce the expression of those E3 ligases (Walter et al., 2014). Thus, further studies are required to identify and characterize putative E3 ligases involved in HIF-2α-mediated pexophagy.


Hypoxia signaling pathways: modulators of oxygen-related organelles.

Schönenberger MJ, Kovacs WJ - Front Cell Dev Biol (2015)

Three alternative models illustrating how HIF-2α might trigger pexophagy. (A) HIF-2α might induce an E3 ubiquitin ligase that ubiquitinates a PMP that enhances the recruitment of the autophagy receptor NBR1 to the peroxisome surface. Accumulation of NBR1 on peroxisomes likely recruits SQSTM1, which was suggested to act as pexophagy co-receptor, and subsequently leads to clustering of peroxisomes via oligomerization of receptor-bound organelles. Accumulation of a critical mass of autophagy receptors might prime phagophore assembly at peroxisomes. (B) NBR1 could be recruited to peroxisomes independently of ubiquitin via its membrane-interacting amphipathic α-helical J domain. HIF-2α might induce or inhibit a kinase/phosphatase that leads to a change in the posttranslational modification of peroxisome-bound NBR1 and thereby triggers recruitment of the autophagic machinery. (C) HIF-2α-dependent activation of pexophagy might be a 2-step process and HIF-2α functions as master regulator that combines two layers of posttranslational modifications to trigger pexophagy. First, it induces an E3 ubiquitin ligase leading to an increased ubiquitination of PMP(s) and subsequent accumulation of NBR1 and SQSTM1 on peroxisomes. Second, HIF-2α activates or inhibits a kinase/phosphatase that leads to a change in the posttranslational modification of peroxisome-bound NBR1 and thereby enhances its binding affinity to a LC3 homolog that finally results in pexophagy. Modified from Schönenberger et al. (2015).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4508581&req=5

Figure 6: Three alternative models illustrating how HIF-2α might trigger pexophagy. (A) HIF-2α might induce an E3 ubiquitin ligase that ubiquitinates a PMP that enhances the recruitment of the autophagy receptor NBR1 to the peroxisome surface. Accumulation of NBR1 on peroxisomes likely recruits SQSTM1, which was suggested to act as pexophagy co-receptor, and subsequently leads to clustering of peroxisomes via oligomerization of receptor-bound organelles. Accumulation of a critical mass of autophagy receptors might prime phagophore assembly at peroxisomes. (B) NBR1 could be recruited to peroxisomes independently of ubiquitin via its membrane-interacting amphipathic α-helical J domain. HIF-2α might induce or inhibit a kinase/phosphatase that leads to a change in the posttranslational modification of peroxisome-bound NBR1 and thereby triggers recruitment of the autophagic machinery. (C) HIF-2α-dependent activation of pexophagy might be a 2-step process and HIF-2α functions as master regulator that combines two layers of posttranslational modifications to trigger pexophagy. First, it induces an E3 ubiquitin ligase leading to an increased ubiquitination of PMP(s) and subsequent accumulation of NBR1 and SQSTM1 on peroxisomes. Second, HIF-2α activates or inhibits a kinase/phosphatase that leads to a change in the posttranslational modification of peroxisome-bound NBR1 and thereby enhances its binding affinity to a LC3 homolog that finally results in pexophagy. Modified from Schönenberger et al. (2015).
Mentions: Since HIF-2α is a transcription factor, the most likely possibility would be that HIF-2α induces the expression of an autophagy receptor and subsequent clustering of peroxisomes via oligomerization of receptor-bound organelles, however, neither Nbr1 nor Sqstm1 are HIF-2α target genes (Walter et al., 2014). Ubiquitination of cargo prone for selective autophagic degradation is the most prevalent autophagy-targeting signal in mammals, and most of the currently known autophagy receptors harbor both ubiquitin-binding domains and LIRs (Kirkin et al., 2009; Stolz et al., 2014). HIF-2α might induce an E3 ubiquitin ligase that mediates the ubiquitination of a PMP (Figure 6A). We propose that HIF-2α signaling increases in this manner NBR1 accumulation on peroxisomes, which in turn serves as a platform for the recruitment of SQSTM1 to achieve a critical mass of autophagy receptors on peroxisomes required for pexophagy (Schönenberger et al., 2015). This might concentrate sufficient ubiquitin-like modifiers (e.g., LC3 and GABARAPs) in close proximity to peroxisomes to prime phagophore assembly. The peroxisomal membrane harbors three E3 ligases (PEX2, PEX10, PEX12) that are essential for peroxisome biogenesis and involved in PEX5 receptor ubiquitination. Their transcriptional induction and concomitant increase of protein levels could increase their ubiquitination capability leading to enhanced ubiquitination of PMPs, but HIF-2α does not induce the expression of those E3 ligases (Walter et al., 2014). Thus, further studies are required to identify and characterize putative E3 ligases involved in HIF-2α-mediated pexophagy.

Bottom Line: We discuss our recent findings that establish HIF-2α as a negative regulator of peroxisome abundance and suggest a mechanism by which cells attune peroxisomal function with O2 availability.HIF-2α activation augments peroxisome turnover by pexophagy and thereby changes lipid composition reminiscent of peroxisomal disorders.We discuss potential mechanisms by which HIF-2α might trigger pexophagy and place special emphasis on the potential pathological implications of HIF-2α-mediated pexophagy for human health.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, Institute of Molecular Health Sciences ETH Zurich, Zurich, Switzerland.

ABSTRACT
Oxygen (O2) is an essential substrate in cellular metabolism, bioenergetics, and signaling and as such linked to the survival and normal function of all metazoans. Low O2 tension (hypoxia) is a fundamental feature of physiological processes as well as pathophysiological conditions such as cancer and ischemic diseases. Central to the molecular mechanisms underlying O2 homeostasis are the hypoxia-inducible factors-1 and -2 alpha (HIF-1α and EPAS1/HIF-2α) that function as master regulators of the adaptive response to hypoxia. HIF-induced genes promote characteristic tumor behaviors, including angiogenesis and metabolic reprogramming. The aim of this review is to critically explore current knowledge of how HIF-α signaling regulates the abundance and function of major O2-consuming organelles. Abundant evidence suggests key roles for HIF-1α in the regulation of mitochondrial homeostasis. An essential adaptation to sustained hypoxia is repression of mitochondrial respiration and induction of glycolysis. HIF-1α activates several genes that trigger mitophagy and represses regulators of mitochondrial biogenesis. Several lines of evidence point to a strong relationship between hypoxia, the accumulation of misfolded proteins in the endoplasmic reticulum, and activation of the unfolded protein response. Surprisingly, although peroxisomes depend highly on molecular O2 for their function, there has been no evidence linking HIF signaling to peroxisomes. We discuss our recent findings that establish HIF-2α as a negative regulator of peroxisome abundance and suggest a mechanism by which cells attune peroxisomal function with O2 availability. HIF-2α activation augments peroxisome turnover by pexophagy and thereby changes lipid composition reminiscent of peroxisomal disorders. We discuss potential mechanisms by which HIF-2α might trigger pexophagy and place special emphasis on the potential pathological implications of HIF-2α-mediated pexophagy for human health.

No MeSH data available.


Related in: MedlinePlus