HSF1 critically attunes proteotoxic stress sensing by mTORC1 to combat stress and promote growth

Su, Kuo‐Hui; Cao, Junyue; Tang, Zijian; Dai, Siyuan; He, Yishu; Sampson, Stephen B.; Benjamin, Ivor J.; Dai, Chengkai

doi:10.1038/ncb3335

Cited by 84 publications

(122 citation statements)

References 62 publications

Supporting

Mentioning

113

Contrasting

Unclassified

Order By: Relevance

“…Previous reports demonstrate that in response to osmotic stress, JNK promotes p70S6K1 phosphorylation at Thr-389 by directly phosphorylating raptor, a component of mTORC1 (38). This is in contrast to a more recent report that JNK contributes to disassociation of mTORC1 via direct phosphorylation of raptor and mTOR in response to proteotoxic stress (39). One possible explanation to reconcile these findings is that JNK-mediated phosphorylation of the p70S6K1 autoinhibitory domain is sufficient to promote mTORC1-dependent phosphorylation of Thr-389 despite attenuated mTORC1 activity (i.e.…”

Section: Discussioncontrasting

confidence: 55%

Activation of the Stress Response Kinase JNK (c-Jun N-terminal Kinase) Attenuates Insulin Action in Retina through a p70S6K1-dependent Mechanism

Miller

Ravi

Martin

et al. 2017

Journal of Biological Chemistry

View full text Add to dashboard Cite

Edited by Jeffrey E. PessinDespite recent advances in therapeutics, diabetic retinopathy remains a leading cause of vision impairment. Improvement in the treatment of diabetic retinopathy requires a better understanding of the molecular mechanisms that cause neurovascular complications, particularly in type 2 diabetes. Recent studies demonstrate that rodents fed a high fat diet exhibit retinal dysfunction concomitant with attenuated Akt phosphorylation. The purpose of the present study was to evaluate the impact of a high fat/high sucrose diet on retinal insulin signaling and evaluate the mechanism(s) responsible for the changes. Mice fed a high fat/sucrose diet exhibited attenuated Akt phosphorylation in the retina as compared with mice fed normal chow. Retinas of mice fed a high fat/sucrose diet also exhibited elevated levels of activated JNK as well as enhanced p70S6K1 autoinhibitory domain phosphorylation. In cells, JNK activation enhanced p70S6K1 phosphorylation and mTORC1-dependent activation of the kinase, as evidenced by enhanced phosphorylation of key substrates. Rictor phosphorylation by p70S6K1 was specifically enhanced by the addition of phosphomimetic mutations in the autoinhibitory domain and was more sensitive to inhibition of the kinase as compared with rpS6. Notably, rictor and IRS-1 phosphorylation by p70S6K1 attenuate insulin action through a negative feedback pathway. Indeed, p70S6K1 inhibition prevented the repressive effect of JNK activation on insulin action in retinas. Overall, the results identify the JNK/S6K1 axis as a key molecular mechanism whereby a high fat/sucrose diet impairs insulin action in retina.Diabetic retinopathy is the leading cause of vision loss in working age Americans. Almost everyone with type 1 diabetes and most people with type 2 diabetes develop retinopathy within two decades of disease onset (1). The incidence of type 2 diabetes is rapidly on the rise and accounts for up to 95% of diabetes prevalence (2). However, the overwhelming majority of experimental studies on diabetic retinopathy have been performed using animal models of type 1 diabetes. Development of type 2 diabetes is associated with consumption of a diet containing high fat and sucrose content, which has become extremely common in Western populations (3). Thus, in the present study we set out to investigate potential mechanisms whereby a Western diet contributes to diabetes-induced vision loss.Diabetic retinopathy is caused by a combination of hyperglycemia and a reduction in insulin-mediated signaling, which results in neurovascular changes in the retina. Insulin provides a protective neurotrophic stimulus to retina by activating the protein kinase Akt through a signaling pathway involving the insulin receptor substrate 1/2 (IRS1/2) 2 (4). In response to insulin, the activation loop of Akt is phosphorylated at Thr-308 by phosphoinositide-dependent kinase 1 (PDK1) (5), whereas the C-terminal hydrophobic motif is phosphorylated at Ser-473 by mTORC2 (mammalian target of rapamycin (mTOR) in complex 2) (6...

show abstract

Section: Discussioncontrasting

confidence: 55%

Activation of the Stress Response Kinase JNK (c-Jun N-terminal Kinase) Attenuates Insulin Action in Retina through a p70S6K1-dependent Mechanism

Miller

Ravi

Martin

et al. 2017

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Since URMC-099 regulates JNK phosphorylation (18), we reasoned that URMC-099 would affect the mechanistic target of mTOR complex 1 (mTORC1) through JNK (21), which in turn would modulate vesicular trafficking through transcription factor EB (TFEB) (22). We found that URMC-099 could affect endosomal trafficking through any one or all of these factors (Supplemental Figure 2A).…”

Section: Urmc-099 Facilitates Nanoart Activitymentioning

confidence: 99%

Autophagy facilitates macrophage depots of sustained-release nanoformulated antiretroviral drugs

Gnanadhas¹,

Dash²,

Sillman³

et al. 2017

Journal of Clinical Investigation

View full text Add to dashboard Cite

Long-acting anti-HIV products can substantively change the standard of care for patients with HIV/AIDS. To this end, hydrophobic antiretroviral drugs (ARVs) were recently developed for parenteral administration at monthly or longer intervals. While shorter-acting hydrophilic drugs can be made into nanocarrier-encased prodrugs, the nanocarrier encasement must be boosted to establish long-acting ARV depots. The mixed-lineage kinase 3 (MLK-3) inhibitor URMC-099 provides this function by affecting autophagy. Here, we have shown that URMC-099 facilitates ARV sequestration and its antiretroviral responses by promoting the nuclear translocation of the transcription factor EB (TFEB). In monocyte-derived macrophages, URMC-099 induction of autophagy led to retention of nanoparticles containing the antiretroviral protease inhibitor atazanavir. These nanoparticles were localized within macrophage autophagosomes, leading to a 4-fold enhancement of mitochondrial and cell vitality. In rodents, URMC-099 activation of autophagy led to 50-fold increases in the plasma drug concentration of the viral integrase inhibitor dolutegravir. These data paralleled URMC-099-mediated induction of autophagy and the previously reported antiretroviral responses in HIV-1-infected humanized mice. We conclude that pharmacologic induction of autophagy provides a means to extend the action of a long-acting, slow, effective release of antiretroviral therapy. Center for Neural Development and Disease, University of Rochester Medical Center (URMC), Rochester, New York, USA. Conflict of interest:H.A. Gelbard and H.E. Gendelman are members of the scientific advisory board for WavoDyne Therapeutics Inc., which is developing URMC-099 as a firstin-class MLK-3 inhibitor for clinical trials. URMC-099 is owned by URMC (patent nos. US 8,846,909 B2;8,877,772;and 9,181,247 and associated international patents). tion of TFEB mRNA by approximately 4-to 8-fold under different treatment conditions ( Figure 2F). With HIV-1 infection, TFEB mRNA levels were reduced by 2-to 3-fold compared with levels in uninfected controls, and URMC-099 could recover the phenotype. Increased TFEB translocation was delayed and did not reach significant levels until day 7 after URMC-099 treatment (Supplemental Figure 2B). These data confirm that URMC-099 regulates TFEB nuclear translocation in an mTORC1-dependent manner. URMC-099 stimulates autophagy in human MDMs. On the basis of the preceding data sets, we theorized that nuclear translocation of TFEB induces autophagy and lysosomal biogenesis. TFEB serves as the master regulator of both autophagy and lysosomal biogenesis (26), and such regulation could have a profound role in nanoART intracellular sequestration in MDMs. Thus, we examined the autophagosome markers microtubule-associated protein 1 light chain 3 β (LC3B, also known as MAP1LC3B) and beclin 1 (BECN1). Using Western blot assays, we found that each marker was significantly upregulated by URMC-099 ( Figure 3, A-C and Supplemental Figure 3A). URMC-099 increased the expression ...

show abstract

“…Mechanistically, our studies unveiled a constitutive association of JNK with mTORC1 even under normal growth conditions 4 . Upon activation, JNK directly phosphorylates both mTOR at Ser567 and regulatory-associated protein of mTOR (RAPTOR) at Ser863 4 . These modifications cause selective exclusion of mTOR and GβL/mLST8 from mTORC1 4 .…”

Section: Jnk Is a Component And Negative Regulator Of Mtorc1mentioning

confidence: 70%

Section: Jnk Is a Component And Negative Regulator Of Mtorc1mentioning

confidence: 76%

“…Our studies revealed that proteotoxic stress activates c-JUN N-terminal kinase (JNK) to suppress mTORC1 and its mediated translation 4 . Mechanistically, our studies unveiled a constitutive association of JNK with mTORC1 even under normal growth conditions 4 . Upon activation, JNK directly phosphorylates both mTOR at Ser567 and regulatory-associated protein of mTOR (RAPTOR) at Ser863 4 .…”

Section: Jnk Is a Component And Negative Regulator Of Mtorc1mentioning

confidence: 85%

See 1 more Smart Citation

Protein quantity-quality balance licenses growth

Dai

2016

Cell Cycle

Self Cite

View full text Add to dashboard Cite

HSF1 critically attunes proteotoxic stress sensing by mTORC1 to combat stress and promote growth

Cited by 84 publications

References 62 publications

Activation of the Stress Response Kinase JNK (c-Jun N-terminal Kinase) Attenuates Insulin Action in Retina through a p70S6K1-dependent Mechanism

Activation of the Stress Response Kinase JNK (c-Jun N-terminal Kinase) Attenuates Insulin Action in Retina through a p70S6K1-dependent Mechanism

Autophagy facilitates macrophage depots of sustained-release nanoformulated antiretroviral drugs

Protein quantity-quality balance licenses growth

Contact Info

Product

Resources

About