Non-apoptotic Caspase regulation of stem cell properties

Baena‐López, Luis Alberto; Arthurton, Lewis; Xu, Derek; Galasso, Alessia

doi:10.1016/j.semcdb.2017.10.034

Cited by 48 publications

(49 citation statements)

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“…Independently, our data supports the hypothesis that non-apoptotic caspase activation is key to modulate fundamental stem cell properties, such as cell proliferation and differentiation, beyond their role in apoptosis [2, 53, 54]. Indeed, considering the fast-growing list of examples indicating an implication for the caspases in non-apoptotic functions [2, 53, 54], apoptosis could be the phenotypically more apparent function of these enzymes, but not necessarily the primary and/or the most relevant. Future evolutionary analysis of these novel non-apoptotic functions in primitive organisms should clarify the primary function of caspases.…”

Section: Discussionsupporting

confidence: 84%

“…These events facilitate the full activation of Dronc [15–18], which subsequently leads to the cleavage of the effector caspases ( Death caspase-1, DCP-1 ( caspase -7); the death related ICE-like caspase, drICE ( caspase -3); Death associated molecule related to Mch2 caspase , Damm and the Death executioner caspase related to Apopain/Yama, Decay ). Upon cleavage, functional effector caspases disrupt all of the essential subcellular structures leading to cell death [2, 6]. Intriguingly, in a previous report we uncovered a stereotyped pattern of non-apoptotic caspase activation in the Drosophila intestine of unknown origin and functional relevance [19].…”

Section: Introductionmentioning

confidence: 99%

“…Caspases are cysteine-dependent aspartate-specific proteases commonly associated with the implementation of apoptosis [1]. Despite this canonical function, an emerging body of evidence is also attributing a non-apoptotic and regulatory role to these enzymes in a wide variety of cell types, including stem cells [2]. However, the caspase-dependent control of intestinal stem cell properties and their contribution to human colon cancers remain poorly characterised.…”

Section: Introductionmentioning

confidence: 99%

“…Accordingly, important discoveries regarding intestinal stem cell biology and caspases have been obtained using this model organism [4]. The caspases are expressed as pro-enzymes that only become fully active after one or more steps of proteolytic processing [1, 2, 5–8]. In Drosophila , the apoptosis programme is initiated by the upregulation of different pro-apoptotic proteins (Hid, Reaper, Grim and/or Sickle) [7–10], which counteract molecular effects of the Drosophila inhibitors of apoptosis, DIAP-1 [11, 12] and -2 [13, 14].…”

Section: Introductionmentioning

confidence: 99%

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Non-apoptotic caspase-dependent regulation of enteroblast quiescence in Drosophila

López

Arthurton²,

Nahotko³

et al. 2019

Preprint

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17Caspase malfunction in stem cells often instigates the appearance and progression of multiple types 18 of cancer, including human colorectal cancer. However, the caspase-dependent regulation of 19intestinal stem cell properties remains poorly understood. Here, we demonstrate that Dronc, the 20Drosophila ortholog of caspase-9/2 in mammals, limits the proliferation of intestinal progenitor cells 21 and prevents the premature differentiation of enteroblasts into enterocytes. Strikingly, these 22

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Section: Discussionsupporting

confidence: 84%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Non-apoptotic caspase-dependent regulation of enteroblast quiescence in Drosophila

López

Arthurton²,

Nahotko³

et al. 2019

Preprint

Self Cite

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“…As CHK1 activation inhibits caspase activity [45], it is tempting to propose that CHK1 indirectly controls STAU2 steady-state levels via the activation/inhibition of caspase activity. Although well characterized for their roles in response to massive DNA damages and induction of apoptosis [46][47][48][49][50], caspases also play other important roles in unstressed cells related to cell proliferation, differentiation and cellular reprogramming [51][52][53]. In turn, CHK1 is involved in cell cycle control, especially during the S phase, where it is required for ring origin of DNA replication [54].…”

Section: Stau2 Protein Is Degraded By Caspases and Stabilized By The mentioning

confidence: 99%

STAU2 Protein Level is Controlled by Caspases and the CHK1 Pathway and Regulates Cell Cycle Progression in the Non-transformed hTERT-RPE1 Cells

Condé

Beaujois

DesGroseillers

2020

Preprint

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Background: Staufen2 (STAU2) is an RNA binding protein involved in the posttranscriptional regulation of gene expression. In neurons, STAU2 is required to maintain the balance between differentiation and proliferation of neural stem cells through asymmetric cell division. However, the importance of controlling STAU2 expression for cell cycle progression is not clear in non-neuronal dividing cells. We recently showed that STAU2 transcription is inhibited in response to DNA-damage due to E2F1 displacement from the STAU2 gene promoter. We now study the regulation of STAU2 steady-state levels in unstressed cells and its consequence for cell proliferation. Results: CRISPR/Cas9-mediated and RNAi-dependent STAU2 depletion in the non-transformed hTERT-RPE1 cells both facilitate cell proliferation suggesting that STAU2 expression influences pathway(s) linked to cell cycle controls. Such effects are not observed in the CRISPR STAU2-KO cancer HCT116 cells nor in the STAU2-RNAi-depleted HeLa cells. Interestingly, a physiological decrease in the steady-state level of STAU2 is controlled by caspases. This effect of peptidases is counterbalanced by the activity of the CHK1 pathway suggesting that STAU2 partial degradation/stabilization fines tune cell cycle progression in unstressed cells. A large-scale proteomic analysis using STAU2/biotinylase fusion protein identifies known STAU2 interactors involved in RNA translation, localization, splicing, or decay confirming the role of STAU2 in the posttranscriptional regulation of gene expression. In addition, several proteins found in the nucleolus, including proteins of the ribosome biogenesis pathway and of the DNA damage response, are found in close proximity to STAU2. Strikingly, many of these proteins are linked to the kinase CHK1 pathway, reinforcing the link between STAU2 functions and the CHK1 pathway. Indeed, inhibition of the CHK1 pathway dissociates STAU1 from proteins involved in translation and RNA metabolism. Conclusions: These results indicate that STAU2 is involved in pathway(s) that control(s) cell proliferation, likely via mechanisms of posttranscriptional regulation, ribonucleoprotein complex assembly, genome integrity and/or checkpoint controls. This novel function of STAU2 is regulated by caspases and by the kinase CHK1 pathway.

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Nonapoptotic role of caspase‐3 in regulating Rho1GTPase‐mediated morphogenesis of epithelial tubes of Drosophila renal system

Ojha

Tapadia

2021

Developmental Dynamics

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Background: Cells trigger caspase-mediated apoptosis to eliminate themselves from the system when tissue needs to be sculptured, or they detect any abnormality within them, thus preventing irreparable damage to the host. However, nonapoptotic activities of caspases are also involved in many cellular functions. Interestingly, Drosophila Malpighian tubules (MTs) express apoptotic proteins, without succumbing to cell death.Results: We show apoptosis-independent role of executioner caspase-3, Drice, in MT morphogenesis. Drice is required for precise cytoskeleton organization and convergent extension, failing which morphology, size, cell number, and arrangement get affected. Furthermore, characteristic stellate cell shape transformation in MTs is also governed by Drice. Genetic interaction study shows that Drice mediates its action by regulating Rho1GTPase functionally, and localization of polarity protein Disc large. Subsequently, downregulation of Rho1GTPase in Drice mutants significantly rescues the cystic MTs phenotype.The study shows a mechanism by which Drice governs tubulogenesis via Rho1GTPase-mediated coordinated organization of actin cytoskeleton and membrane stabilization. Conclusion: Collectively our findings suggest a nonapoptotic function of caspase-3 in fine-tuning of cellular rearrangement during tubule development, and these results will add to the growing understanding of diverse roles of caspases during its evolution in metazoans.

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Non-apoptotic Caspase regulation of stem cell properties

Abstract: HighlightsGeneral overview of the caspase protein family.Stem cells: fundamental concepts.Caspase roles in embryonic and Induced pluripotent stem cells.Caspase roles in adult stem cells.Pathological consequences of caspase deregulation and therapeutic potential of caspase modulation.

Cited by 48 publications

References 113 publications

Non-apoptotic caspase-dependent regulation of enteroblast quiescence in Drosophila

Non-apoptotic caspase-dependent regulation of enteroblast quiescence in Drosophila

STAU2 Protein Level is Controlled by Caspases and the CHK1 Pathway and Regulates Cell Cycle Progression in the Non-transformed hTERT-RPE1 Cells

Nonapoptotic role of caspase‐3 in regulating Rho1GTPase‐mediated morphogenesis of epithelial tubes of Drosophila renal system

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