Heat shock factor 4 regulates lens epithelial cell homeostasis by working with lysosome and anti-apoptosis pathways

Cui, Xiukun; Liu, Huiyuan; Li, Jing; Guo, Kangwen; Han, Wenxiu; Dong, Yi; Wan, Simin; Wang, Xuance; Jia, Pan‐Pan; Li, Shulian; Ma, Yuanfang; Zhang, Jun; Mu, Hongmei; Hu, Yanzhong

doi:10.1016/j.biocel.2016.08.022

Cited by 17 publications

(13 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our previous studies have shown that HSF4 can upregulate lysosome activity in HLECs. 57 Furthermore, the p53 and Bax could increase the lysosome membrane permeabilization to trigger cell death. Thus, the accumulation of matured LE in the hsf4 null lens might be caused by the decreased activity of lysosome.…”

Section: Discussionmentioning

confidence: 99%

HSF4 regulates lens fiber cell differentiation by activating p53 and its downstream regulators

et al. 2017

View full text Add to dashboard Cite

Cataract refers to opacities of the lens that impede the passage of light. Mutations in heat shock transcription factor 4 (HSF4) have been associated with cataract; however, the mechanisms regarding how mutations in HSF4 cause cataract are still obscure. In this study, we generated an hsf4 knockout zebrafish model using TALEN technology. The mutant zebrafish developed an early-onset cataract with multiple developmental defects in lens. The epithelial cells of the lens were overproliferated, resulting in the overabundance of lens fiber cells in hsf4null zebrafish lens. Consequently, the arrangement of the lens fiber cells became more disordered and irregular with age. More importantly, the terminal differentiation of the lens fiber cell was interrupted as the organelles cannot be cleaved in due time. In the cultured human lens epithelial cells, HSF4 could stabilize and retain p53 in the nucleus to activate its target genes such as fas cell surface death receptor (Fas) and Bcl-2-associated X apoptosis regulator (Bax). In the hsf4null fish, both p53 and activated-caspase3 were significantly decreased. Combined with the finding that the denucleation defect could be partially rescued through microinjection of p53, fas and bax mRNA into the mutant embryos, we directly proved that HSF4 promotes lens fiber cell differentiation by activating p53 and its downstream regulators. The data we presented suggest that apoptosis-related genes are involved in the lens fiber cell differentiation. Our finding that HSF4 functions in the upstream to activate these genes highlighted the new regulatory modes of HSF4 in the terminal differentiation of lens fiber cell.

show abstract

Section: Discussionmentioning

confidence: 99%

HSF4 regulates lens fiber cell differentiation by activating p53 and its downstream regulators

et al. 2017

View full text Add to dashboard Cite

show abstract

“…Studies have been able to link crystallins (CRYBA1 and CRAYAB) to ATP6V1A expression. ATP6Va1 is a subunit of the vacuolar H+ATPase (V-ATPase) necessary for lysosomal acidification and also for autophagy 84,85 . Our proteomics analysis shows decreased ATP6Va1 in Ambra1 +/gt retinae, as well as other proteins involved in phagosome maturation.…”

Section: Discussionmentioning

confidence: 99%

Age related retinal Ganglion cell susceptibility in context of autophagy deficiency

et al. 2020

View full text Add to dashboard Cite

Glaucoma is a common age-related disease leading to progressive retinal ganglion cell (RGC) death, visual field defects and vision loss and is the second leading cause of blindness in the elderly worldwide. Mitochondrial dysfunction and impaired autophagy have been linked to glaucoma and induction of autophagy shows neuroprotective effects in glaucoma animal models. We have shown that autophagy decreases with aging in the retina and that autophagy can be neuroprotective for RGCs, but it is currently unknown how aging and autophagy deficiency impact RGCs susceptibility and survival. Using the optic nerve crush model in young and olWelcome@1234d Ambra1 +/gt (autophagy/beclin-1 regulator 1 +/gt) mice we analysed the contribution of autophagy deficiency on retinal ganglion cell survival in an age dependent context. Interestingly, old Ambra1 +/gt mice showed decreased RGC survival after optic nerve crush in comparison to old Ambra1 +/+ , an effect that was not observed in the young animals. Proteomics and mRNA expression data point towards altered oxidative stress response and mitochondrial alterations in old Ambra1 +/gt animals. This effect is intensified after RGC axonal damage, resulting in reduced oxidative stress response showing decreased levels of Nqo1, as well as failure of Nrf2 induction in the old Ambra1 +/gt. Old Ambra1 +/gt also failed to show increase in Bnip3l and Bnip3 expression after optic nerve crush, a response that is found in the Ambra1 +/+ controls. Primary RGCs derived from Ambra1 +/gt mice show decreased neurite projection and increased levels of apoptosis in comparison to Ambra1 +/+ animals. Our results lead to the conclusion that oxidative stress response pathways are altered in old Ambra1 +/gt mice leading to impaired damage responses upon additional external stress factors.

show abstract

“…Proteolytic machinery, like the lysosomal degradation pathway, plays essential roles in supporting lens epithelium proteostasis as well as the fiber cell terminal differentiation and nuclear degradation [69]. In line with this, the HSF4-crystallin axis is involved in maintaining the optimal level of lysosomal acidification in the lens cells by preventing the lysosomal transmembrane proton pump ATP6V1A from being degraded by the ubiquitinmediated proteasomal degradation pathway [70,71]. Mechanistically, crystallin formed a protein complex with ATP6V1A and mTORC1, whereby the inhibition of HSF4, crystallin, or mTORC1 led to the dissociation of this complex and ATP6V1A destabilization, which consequently increased the lysosomal pH level [71].…”

Section: Lens Cell Homeostasismentioning

confidence: 91%

More Than Meets the Eye: Revisiting the Roles of Heat Shock Factor 4 in Health and Diseases

et al. 2021

View full text Add to dashboard Cite

Cells encounter a myriad of endogenous and exogenous stresses that could perturb cellular physiological processes. Therefore, cells are equipped with several adaptive and stress-response machinery to overcome and survive these insults. One such machinery is the heat shock response (HSR) program that is governed by the heat shock factors (HSFs) family in response towards elevated temperature, free radicals, oxidants, and heavy metals. HSF4 is a member of this HSFs family that could exist in two predominant isoforms, either the transcriptional repressor HSFa or transcriptional activator HSF4b. HSF4 is constitutively active due to the lack of oligomerization negative regulator domain. HSF4 has been demonstrated to play roles in several physiological processes and not only limited to regulating the classical heat shock- or stress-responsive transcriptional programs. In this review, we will revisit and delineate the recent updates on HSF4 molecular properties. We also comprehensively discuss the roles of HSF4 in health and diseases, particularly in lens cell development, cataract formation, and cancer pathogenesis. Finally, we will posit the potential direction of HSF4 future research that could enhance our knowledge on HSF4 molecular networks as well as physiological and pathophysiological functions.

show abstract

Heat shock factor 4 regulates lens epithelial cell homeostasis by working with lysosome and anti-apoptosis pathways

Cited by 17 publications

References 33 publications

HSF4 regulates lens fiber cell differentiation by activating p53 and its downstream regulators

HSF4 regulates lens fiber cell differentiation by activating p53 and its downstream regulators

Age related retinal Ganglion cell susceptibility in context of autophagy deficiency

More Than Meets the Eye: Revisiting the Roles of Heat Shock Factor 4 in Health and Diseases

Contact Info

Product

Resources

About