Surviving protein quality control catastrophes – from cells to organisms

Schneider, Kim; Bertolotti, Anne

doi:10.1242/jcs.173047

Cited by 52 publications

(52 citation statements)

References 79 publications

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“…However, their expression levels were upregulated when protein folding at the ER was disrupted. 48 In this study, the neuroprotective effect of FGF2-dscECM-HP was related to the inhibition of chronic ER stress-induced apoptosis. The survival of sensory neurons and axon regeneration in spinal cord lesions was also highly associated with the inhibition of endoplasmic reticulum stress.…”

Section: Discussionmentioning

confidence: 73%

Sustained-release of FGF-2 from a hybrid hydrogel of heparin-poloxamer and decellular matrix promotes the neuroprotective effects of proteins after spinal injury

Xu¹,

Tian²,

Xiao³

et al. 2018

IJN

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Introduction The short lifetime of protein-based therapies has largely limited their therapeutic efficacy in injured nervous post-spinal cord injury (post-SCI). Methods In this study, an affinity-based hydrogel delivery system provided sustained-release of proteins, thereby extending the efficacy of such therapies. The affinity-based hydrogel was constructed using a novel polymer, heparin-poloxamer (HP), as a temperature-sensitive bulk matrix and decellular spinal cord extracellular matrix (dscECM) as an affinity depot of drug. By tuning the concentration of HP in formulation, the cold ternary fibroblast growth factor-2 (FGF2)-dscECM-HP solution could rapidly gelatinize into a hydrogel at body temperature. Due to the strong affinity for FGF2, hybrid FGF2-dscECM-HP hydrogel enabled sustained-release of encapsulated FGF2 over an extended period in vitro. Results Compared to free FGF2, it was observed that both neuron functions and tissue morphology after SCI were clearly recovered in rats treated with FGF2-dscECM-HP hydrogel. Moreover, the expression of neurofilament protein and the density of axons were increased after treatment with hybrid FGF2-dscECM-HP. In addition, the neuroprotective effects of FGF2-dscECM-HP were related to inhibition of chronic endoplasmic reticulum stress-induced apoptosis. Conclusion The results revealed that a hybrid hydrogel system may be a potential carrier to deliver macromolecular proteins to the injured site and enhance the therapeutic effects of proteins.

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Section: Discussionmentioning

confidence: 73%

Sustained-release of FGF-2 from a hybrid hydrogel of heparin-poloxamer and decellular matrix promotes the neuroprotective effects of proteins after spinal injury

Xu¹,

Tian²,

Xiao³

et al. 2018

IJN

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“…Therefore, we cannot exclude that Bcl-2 IV/GG is intrinsically toxic to cells, but we postulate that toxicity is mostly avoided by the rapid turnover of the Bcl-2 IV/GG mutant protein. Somewhat unexpectedly, expression of the highly unstable Bcl-2 IV/GG did not induce a marked UPR response ( [68,69]; Fig. 6A).…”

Section: Discussionmentioning

confidence: 90%

A double point mutation at residues Ile14 and Val15 of Bcl‐2 uncovers a role for the BH4 domain in both protein stability and function

et al. 2017

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B-cell lymphoma 2 (Bcl-2) protein is the archetype apoptosis suppressor protein. The N-terminal Bcl-2-homology 4 (BH4) domain of Bcl-2 is required for the antiapoptotic function of this protein at the mitochondria and endoplasmic reticulum (ER). The involvement of the BH4 domain in Bcl-2 0 s antiapoptotic functions has been proposed based on Gly-based substitutions of the Ile14/Val15 amino acids, two hydrophobic residues located in the center of Bcl-2 0 s BH4 domain. Following this strategy, we recently showed that a BH4-domain-derived peptide in which Ile14 and Val15 have been replaced by Gly residues, was unable to dampen proapoptotic Ca 2+ -release events from the ER. Here, we investigated the impact of these mutations on the overall structure, stability, and function of full-length Bcl-2 as a regulator of Ca 2+ signaling and cell death. Our results indicate that full-length Bcl-2 Ile14Gly/Val15Gly, in contrast to wild-type Bcl-2, (a) displayed severely reduced structural stability and a shortened protein halflife; (b) failed to interact with Bcl-2-associated X protein (BAX), to inhibit the inositol 1,4,5-trisphosphate receptor (IP 3 R) and to protect against Ca 2+ -mediated apoptosis. We conclude that the hydrophobic face of Bcl-2 0 s BH4 domain (Ile14, Val15) is an important structural regulatory element by affecting protein stability and turnover, thereby likely reducing Bcl-2 0 s ability to modulate the function of its targets, like IP 3 R and BAX. Therefore, Bcl-2 structure/function studies require pre-emptive and reliable determination of protein stability upon introduction of point mutations at the level of the BH4 domain. IntroductionApoptotic cell death is rigorously controlled by the intracellular ratio of anti-and pro-apoptotic B-cell lymphoma 2 (Bcl-2) proteins, a family of globular proteins acting upstream of mitochondrial outer membrane permeabilization (MOMP) and the cytosolic release of apoptogenic factors. Antiapoptotic Bcl-2 proteins, such as Bcl-2, B-cell lymphoma-extra large (Bcl-XL), and myeloid cell leukemia-1 (Mcl-1), guarantee cell survival mainly by neutralizing the pro-MOMP activity of their proapoptotic relatives [e.g., Bcl-2-associated X protein (BAX), Bcl-2 homologous antagonist killer (BAK)] at the mitochondria and by simultaneously restraining the flux of Ca 2+ ions between endoplasmic reticulum (ER) and mitochondria [1][2][3]. Bcl-2 and its prosurvival relatives contain all four of the structurally conserved and functionally essential a-helical regions defined as Bcl-2-homology domains (BH; Fig. 1A,B, upper panel). The most N-terminal BH region, the BH4 domain, distinguishes these antiapoptotic proteins from some, but not all, of their proapoptotic counterparts [4,5]. Interestingly, recent studies revealed that the BH4 helix, either as isolated peptide [6-10], or as an integral part of full-length Bcl-2 [11-16] possesses an antiapoptotic activity separated from or additive to the one mediated by the other three BH domains (BH1-3). At the mitochondria, the BH4 domain of Bcl-2 p...

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“…Slowing down translation rates can significantly improve protein folding, therefore contributing to reestablishment of homeostasis in these diseases (67)(68)(69). Drugs such as Salubrinal (11) and Guanabenz (13) or Sephin 1 (70), which were described as selective inhibitors of cellular complexes that dephosphorylate eIF2α, have been considered toward that purpose and showed promising results in animals.…”

Section: Discussionmentioning

confidence: 99%

An inhibitor of HIV-1 protease modulates constitutive eIF2α dephosphorylation to trigger a specific integrated stress response

Gassart

Bujisic

Zaffalon

et al. 2015

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

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Inhibitors of the HIV aspartyl protease [HIV protease inhibitors (HIV-PIs)] are the cornerstone of treatment for HIV. Beyond their well-defined antiretroviral activity, these drugs have additional effects that modulate cell viability and homeostasis. However, little is known about the virus-independent pathways engaged by these molecules. Here we show that the HIV-PI Nelfinavir decreases translation rates and promotes a transcriptional program characteristic of the integrated stress response (ISR). Mice treated with Nelfinavir display hallmarks of this stress response in the liver, including α subunit of translation initiation factor 2 (eIF2α) phosphorylation, activating transcription factor-4 (ATF4) induction, and increased expression of known downstream targets. Mechanistically, Nelfinavir-mediated ISR bypassed direct activation of the eIF2α stress kinases and instead relied on the inhibition of the constitutive eIF2α dephosphorylation and down-regulation of the phophatase cofactor CReP (Constitutive Repressor of eIF2α Phosphorylation; also known as PPP1R15B). These findings demonstrate that the modulation of eIF2α-specific phosphatase cofactor activity can be a rheostat of cellular homeostasis that initiates a functional ISR and suggest that the HIV-PIs could be repositioned as therapeutics in human diseases to modulate translation rates and stress responses.

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Surviving protein quality control catastrophes – from cells to organisms

Cited by 52 publications

References 79 publications

Sustained-release of FGF-2 from a hybrid hydrogel of heparin-poloxamer and decellular matrix promotes the neuroprotective effects of proteins after spinal injury

Sustained-release of FGF-2 from a hybrid hydrogel of heparin-poloxamer and decellular matrix promotes the neuroprotective effects of proteins after spinal injury

A double point mutation at residues Ile14 and Val15 of Bcl‐2 uncovers a role for the BH4 domain in both protein stability and function

An inhibitor of HIV-1 protease modulates constitutive eIF2α dephosphorylation to trigger a specific integrated stress response

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