K63 linked ubiquitin chain formation is a signal for HIF1A degradation by Chaperone-Mediated Autophagy

Ferreira, João Vasco; Soares, Amílcar; Ramalho, José S.; Pereira, Paulo; Girão, Henrique

doi:10.1038/srep10210

Cited by 83 publications

(82 citation statements)

References 46 publications

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“…This process is also contingent upon Lys-63-linked ubiquitination of HIF-1␣ by the ubiquitin E3 ligase STUB1 (18). Lysosomal degradation of HIF-1␣ is activated by nutrient deprivation, and in livers extracted from starved animals, the localization of HIF-1␣ in lysosomes is increased (17,18). In the context of our results, the acidic pH conditions extant in hypercapnia may deprive cells nutritionally, and they respond to this challenge by lysosomally degrading HIF-␣ protein.…”

Section: Discussionsupporting

confidence: 50%

“…Recently, an O 2 -independent mechanism of HIF protein degradation has been described involving lysosomes (15)(16)(17)(18). Because an acidic environment is optimal for lysosomal functioning, we focused on this particular non-canonical HIF degradative pathway (37).…”

Section: Resultsmentioning

confidence: 99%

“…The chaperone protein HSPA8 and the lysosome membrane receptor LAMP2A have been implicated in the lysosomal degradation of HIF-1␣ (17). This process is also contingent upon Lys-63-linked ubiquitination of HIF-1␣ by the ubiquitin E3 ligase STUB1 (18). Lysosomal degradation of HIF-1␣ is activated by nutrient deprivation, and in livers extracted from starved animals, the localization of HIF-1␣ in lysosomes is increased (17,18).…”

Section: Discussionmentioning

confidence: 99%

“…HIF regulates the transcription of a host of targets, including those with angiogenic, vasodilatory, inflammatory, and glycolytic functions (13)(14). Recently, evidence has emerged for a separate O 2 -independent, non-canonical HIF degradation pathway that is reliant on chaperone-mediated lysosomal autophagy (15)(16)(17)(18).…”

mentioning

confidence: 99%

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Hypercapnia Suppresses the HIF-dependent Adaptive Response to Hypoxia

Selfridge¹,

Cavadas

Scholz³

et al. 2016

Journal of Biological Chemistry

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Molecular oxygen and carbon dioxide are the primary gaseous substrate and product of oxidative metabolism, respectively. Hypoxia (low oxygen) and hypercapnia (high carbon dioxide) are co-incidental features of the tissue microenvironment in a range of pathophysiologic states, including acute and chronic respiratory diseases. The hypoxia-inducible factor (HIF) is the master regulator of the transcriptional response to hypoxia; however, little is known about the impact of hypercapnia on gene transcription. Because of the relationship between hypoxia and hypercapnia, we investigated the effect of hypercapnia on the HIF pathway. Hypercapnia suppressed HIF-␣ protein stability and HIF target gene expression both in mice and cultured cells in a manner that was at least in part independent of the canonical O 2 -dependent HIF degradation pathway. The suppressive effects of hypercapnia on HIF-␣ protein stability could be mimicked by reducing intracellular pH at a constant level of partial pressure of CO 2 . Bafilomycin A1, a specific inhibitor of vacuolar-type H ؉ -ATPase that blocks lysosomal degradation, prevented the hypercapnic suppression of HIF-␣ protein. Based on these results, we hypothesize that hypercapnia counter-regulates activation of the HIF pathway by reducing intracellular pH and promoting lysosomal degradation of HIF-␣ subunits. Therefore, hypercapnia may play a key role in the pathophysiology of diseases where HIF is implicated.Current atmospheric CO 2 levels are relatively low when compared with those recorded throughout the natural history of the planet (1). Not surprisingly, therefore, a range of organisms as diverse as bacteria, fungi, plants, and mammals mount physiologic responses to hypercapnia (2). It is now clear that CO 2 , like other physiologic gases such as oxygen and nitric oxide, can be sensed by cells and can elicit adaptive transcriptional responses (2-4).Because O 2 consumption is coupled to CO 2 production, an intimate inverse relationship exists between the levels of these gases in cells and tissues. Furthermore, O 2 and CO 2 levels may become perturbed during certain pathophysiologic states (3, 5). Hypoxia and hypercapnia can co-occur in respiratory disorders such as obstructive sleep apnea syndrome, pneumonia, and chronic obstructive pulmonary disease (6, 7). In acute lung injury hypoxia may arise, whereas permissive hypercapnia is often tolerated as a protective ventilatory strategy in patients presenting with this disorder (8, 9). Hypercapnia and hypoxia also influence inflammatory processes (10 -12). During inflammation, oxygen consumption is significantly elevated, leading to tissue hypoxia. It is likely that this also has consequences for tissue CO 2 levels (3, 11). HIF 8 (which comprises the HIF-1, HIF-2, and HIF-3 isoforms) is the master transcriptional regulator of the cellular response to hypoxia (13). Canonical HIF degradation relies on the activity of O 2 -dependent prolyl hydroxylases 1-3 (14). In normoxia, prolyl hydroxylases enzymatically modify HIF-␣ subunits on proli...

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Section: Discussionsupporting

confidence: 50%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Hypercapnia Suppresses the HIF-dependent Adaptive Response to Hypoxia

Selfridge¹,

Cavadas

Scholz³

et al. 2016

Journal of Biological Chemistry

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“…6 Furthermore, STUB1 mediated K63 ubiquitination in an oxygen-independent manner and was required for HIF1a degradation via CMA. 7 We identified a canonical KFERQ motif (LDKFQ) and a putative KFERQ motif (QVKVY, if Y gets phosphorylated) in human HIF2a, which raises the possibility that CMA also mediates HIF2a degradation in a similar manner. Further experiments performing site-directed mutagenesis CONTACT Eric Jonasch ejonasch@mdanderson.org; Xian-De Liu xliu10@mdanderson.org in both KFERQ motifs and genetic inactivation of CMA and STUB1 will be required to confirm this possibility.…”

mentioning

confidence: 92%

Autophagy degrades hypoxia inducible factors

DePavia

Jonasch

Liu

2016

Molecular & Cellular Oncology

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Lysosome‐dependent FOXA1 ubiquitination contributes to luminal lineage of advanced prostate cancer

Celada,

Li,

Celada

et al. 2023

Molecular Oncology

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Changes in FOXA1 (forkhead box protein A1) protein levels are well associated with prostate cancer (PCa) progression. Unfortunately, direct targeting of FOXA1 in progressive PCa remains challenging due to variations in FOXA1 protein levels, increased FOXA1 mutations at different stages of PCa, and elusive post‐translational FOXA1 regulating mechanisms. Here, we show that SKP2 (S‐phase kinase‐associated protein 2) catalyzes K6‐ and K29‐linked polyubiquitination of FOXA1 for lysosomal‐dependent degradation. Our data indicate increased SKP2:FOXA1 protein ratios in stage IV human PCa compared to stages I‐III, together with a strong inverse correlation (r=‐0.9659) between SKP2 and FOXA1 levels, suggesting that SKP2‐FOXA1 protein interactions play a significant role in PCa progression. Prostate tumors of Pten/Trp53 mice displayed increased Skp2‐Foxa1‐Pcna signaling and colocalization, whereas disruption of the Skp2‐Foxa1 interplay in Pten/Trp53/Skp2 triple‐null mice demonstrated decreased Pcna levels and increased expression of Foxa1 and luminal positive cells. Treatment of xenograft mice with the SKP2 inhibitor SZL P1‐41 decreased tumor proliferation, SKP2:FOXA1 ratios and colocalization. Thus, our results highlight the significance of the SKP2‐FOXA1 interplay on the luminal lineage in PCa and the potential of therapeutically targeting FOXA1 through SKP2 to improve PCa control.

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K63 linked ubiquitin chain formation is a signal for HIF1A degradation by Chaperone-Mediated Autophagy

Cited by 83 publications

References 46 publications

Hypercapnia Suppresses the HIF-dependent Adaptive Response to Hypoxia

Hypercapnia Suppresses the HIF-dependent Adaptive Response to Hypoxia

Autophagy degrades hypoxia inducible factors

Lysosome‐dependent FOXA1 ubiquitination contributes to luminal lineage of advanced prostate cancer

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