Hsp70 and CHIP Selectively Mediate Ubiquitination and Degradation of Hypoxia-inducible Factor (HIF)-1α but Not HIF-2α

Luo, Weibo; Zhong, Jun; Chang, Ryan; Hu, Hongxia; Pandey, Akhilesh; Semenza, Gregg L.

doi:10.1074/jbc.m109.068577

Cited by 194 publications

(173 citation statements)

References 36 publications

(57 reference statements)

Supporting

Mentioning

163

Contrasting

Unclassified

Order By: Relevance

“…Previous work from our group identified HSP70, a protein with a high degree of sequence similarity to HSC70, as a regulator of HIF-1␣ degradation (24). However, HSP70 is involved in proteasomal degradation of HIF-1␣ rather than lysosomal degradation.…”

Section: Discussionmentioning

confidence: 95%

“…Hydroxylase activity can be inhibited by iron chelators, such as desferrioxamine (DFX), and by competitive antagonists of ␣-ketoglutarate, such as dimethyloxalylglycine, because the hydroxylases contain Fe(II) in their catalytic centers and use ␣-ketoglutarate as a co-substrate (14). In recent years, proteins that regulate proteasomal degradation of HIF-1␣ in an O 2 -independent fashion have also been identified, including RACK1 (21), calcineurin (22), hypoxia-associated factor (23), CHIP/HSP70 (24), and SHARP1 (25).…”

Section: Hypoxia-inducible Factor-1 (Hif-1)mentioning

confidence: 99%

See 1 more Smart Citation

Chaperone-mediated Autophagy Targets Hypoxia-inducible Factor-1α (HIF-1α) for Lysosomal Degradation

Hubbi

Kshitiz

et al. 2013

Journal of Biological Chemistry

Self Cite

200

177

View full text Add to dashboard Cite

Background: Regulation of hypoxia-inducible factor-1 (HIF-1) is focused on proteasomal degradation of the HIF-1␣ subunit. Results: Pharmacological and genetic approaches establish that HIF-1␣ binds to effectors of chaperone-mediated autophagy (CMA) and is targeted for lysosomal degradation. Conclusion: CMA targets HIF-1␣ for lysosomal degradation. Significance: Lysosomal degradation of HIF-1␣ represents a novel mechanism of HIF-1 regulation and a potential therapeutic target.

show abstract

Section: Discussionmentioning

confidence: 95%

Section: Hypoxia-inducible Factor-1 (Hif-1)mentioning

confidence: 99%

Chaperone-mediated Autophagy Targets Hypoxia-inducible Factor-1α (HIF-1α) for Lysosomal Degradation

Hubbi

Kshitiz

et al. 2013

Journal of Biological Chemistry

Self Cite

200

177

View full text Add to dashboard Cite

show abstract

“…Recently it was reported that the E3 ligase STUB1 is involved in the proteasomal degradation of HIF1A. 10,11 Furthermore, STUB1 is known to interact with elements of the molecular chaperone machinery (including HSPA8). [35][36][37] To address if STUB1 is involved in the shuttling of HIF1A to CMA degradation, ARPE-19 cells were transfected with plasmids encoding STUB1 fused to a myc tag.…”

Section: Resultsmentioning

confidence: 99%

“…8 However, more recent evidence indicates that the degradation of HIF1A may also occur through alternative pathways. For example the GNB2L1/RACK1-Elongin-C-Elongin-B complex 9 and the co-chaperone STIP1 homology and U box-containing protein 1 STUB1/CHIP 10,11 were both shown to mediate the ubiquitinylation and subsequent proteasomal degradation of HIF1A in an oxygen-independent manner. Moreover, recent reports began to unveil a role for the lysosome in the degradation of HIF1A.…”

Section: Introductionmentioning

confidence: 99%

STUB1/CHIP is required for HIF1A degradation by chaperone-mediated autophagy

Fofo²,

et al. 2013

View full text Add to dashboard Cite

The transcription factor hiF1 is mostly regulated by the oxygen-dependent proteasomal degradation of the labile subunit hiF1A. recent data showed degradation of hiF1A in the lysosome through chaperone-mediated autophagy (cMA). however the molecular mechanism involved has not been elucidated. This study shows that the KFerQ-like motif, that has been identified in all cMA substrates, is required to mediate the interaction between hiF1A and the chaperone hSpA8. Moreover, mutations in the KFerQ-like motif of hiF1A preclude the interaction with the cMA receptor LAMp2A, thus inhibiting its lysosomal degradation. importantly, we show for the first time that the ubiquitin ligase STUB1 is required for degradation of hiF1A in the lysosome by cMA. indeed, mutations in STUB1 that inhibit either the ubiquitin ligase activity or its ability to bind to hSpA8, both prevent degradation of hiF1A by cMA. Moreover, we show that hiF1A binds to and is translocated into intact lysosomes isolated from rat livers. This new pathway for degradation of hiF1A does not depend on the presence of oxygen and is activated in response to nutrient deprivation such that the levels of hiF1A bound to cMA positive lysosomes significantly increase in starved animal livers and the binding of hiF1A to LAMp2A increases in response to serum deprivation. Moreover, excessive degradation of hiF1A by cMA compromises cells' ability to respond to and survive under hypoxia, suggesting that this pathway might be of pathophysiological importance in conditions that combine hypoxia with starvation. leucinylleucinylleucinal/proteasome inhibitor; MTT, 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide; RCC, renal cell carcinoma; Serpinb, serpin peptidase inhibitor, clade B/Ovalbumin; SLC2A1, solute carrier family 2 (facilitated glucose transporter)/glucose transporter; STUB1, STIP1 homology and U-box containing protein 1; TPR, tetratricopeptide repeat; UPS, ubiquitin-proteasome system; VEGFA, vascular endothelial growth factor A; u-box, modified RING finger domain lacking the metal-chelating residues

show abstract

“…HIF-2, which is composed of HIF-2α and HIF-1β subunits, is regulated by oxygen in a similar manner, although HIF-2 has a more limited tissue distribution and in some cases regulates distinct target genes (15). Mechanisms by which HIF-1α is regulated in an O 2 -independent manner have also been identified (16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26). In addition to proteasome-dependent pathways for HIF-1α degradation, we identified a pathway by which HIF-1α can be targeted for lysosomal degradation through chaperonemediated autophagy (27), which subsequently was confirmed by others (28)(29)(30).…”

mentioning

confidence: 97%

Cyclin-dependent kinases regulate lysosomal degradation of hypoxia-inducible factor 1α to promote cell-cycle progression

Hubbi¹,

Gilkes

Hu³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that mediates adaptive responses to oxygen deprivation. In addition, the HIF-1α subunit has a nontranscriptional role as a negative regulator of DNA replication through effects on minichromosome maintenance helicase loading and activation. However, some cell types continue to replicate under hypoxic conditions. The mechanism by which these cells maintain proliferation in the presence of elevated HIF-1α levels is unclear. Here we report that HIF-1α physically and functionally interacts with cyclin-dependent kinase 1 (Cdk1) and Cdk2. Cdk1 activity blocks lysosomal degradation of HIF-1α and increases HIF-1α protein stability and transcriptional activity. By contrast, Cdk2 activity promotes lysosomal degradation of HIF-1α at the G1/S phase transition. Blocking lysosomal degradation by genetic or pharmacological means leads to HIF-1α-dependent cell-cycle arrest, demonstrating that lysosomal degradation of HIF-1α is an essential step for the maintenance of cell-cycle progression under hypoxic conditions. cell proliferation | chaperone mediated autophagy | lysosome

show abstract

Hsp70 and CHIP Selectively Mediate Ubiquitination and Degradation of Hypoxia-inducible Factor (HIF)-1α but Not HIF-2α

Cited by 194 publications

References 36 publications

Chaperone-mediated Autophagy Targets Hypoxia-inducible Factor-1α (HIF-1α) for Lysosomal Degradation

Chaperone-mediated Autophagy Targets Hypoxia-inducible Factor-1α (HIF-1α) for Lysosomal Degradation

STUB1/CHIP is required for HIF1A degradation by chaperone-mediated autophagy

Cyclin-dependent kinases regulate lysosomal degradation of hypoxia-inducible factor 1α to promote cell-cycle progression

Contact Info

Product

Resources

About