Endoplasmic reticulum stress-induced caspase-4 activation mediates apoptosis and neurodegeneration in INCL

Kim, Sung-Jo; Zhang, Zhongjian; Hitomi, Emiko; Lee, Yi-Ching; Mukherjee, Anil B.

doi:10.1093/hmg/ddl105

Cited by 134 publications

(109 citation statements)

References 30 publications

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“…This cleavage triggers the downstream caspase-3/7 pathway, which cleaves TDP-43 more efficiently and results in the formation of CTF aggregates and the induction of ER stress. Indeed, previous reports suggest that at least caspase-3 is activated by caspase-4 as a downstream effector caspase 33,34 . It is currently unknown why caspase-4 recognizes Asp174 more efficiently than Asp89 in vivo, even though caspase-4 can generate CTF35 more efficiently than CTF25 in vitro.…”

Section: Discussionmentioning

confidence: 99%

The cleavage pattern of TDP-43 determines its rate of clearance and cytotoxicity

et al. 2015

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TAR DNA-binding protein of 43 kDa (TDP-43) and its C-terminal fragment of 25 kDa (CTF25) play critical roles in amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Although the overexpression of TDP-43 in cultured cells and animals results in the production of CTF25, the cleavage site that generates CTF25 and biological significance of the cleavage remain undetermined. Here we identify Asp174 as a cleavage site for CTF25. TDP-43 is cleaved initially after Asp174, which activates caspase-3/7 to accelerate TDP-43 fragmentation. Consequently, blockage of this cleavage results in a severe delay in TDP-43 clearance and prolonged necrotic cell death. We further show that the endoplasmic reticulum membrane-bound caspase-4 is the enzyme responsible for the cleavage after Asp174 and inhibition of caspase-4 activity slows TDP-43 fragmentation and reduces cell viability. These findings suggest that caspase-4-mediated cleavage after Asp174 is an initiator of TDP-43 clearance, which is required to avoid cell death induced by overexpressed TDP-43. A myotrophic lateral sclerosis (ALS) is one of the most devastating neurodegenerative diseases and is characterized by muscle weakness due to the degeneration of both upper and lower motor neurons. Although the pathogenic mechanism of ALS remains unresolved, the RNA-binding protein TDP-43 has been shown to accumulate in cytoplasmic inclusions in the affected regions of the spinal cord and brain in patients with ALS and frontotemporal lobar degeneration (FTLD), respectively 1,2 . Subsequently, mutations linked with ALS and FTLD have been identified in the gene that encodes TDP-43, which has confirmed the significance of TDP-43 in the pathogenesis of these diseases 3,4 . Most of these mutations occur within or near the carboxyl-terminal (C-terminal) glycine-rich domain (GRD) of TDP-43, except for the D169G point mutation that resides in RNA recognition motif 1 (refs 3,4). TDP-43 is normally localized predominantly in the nucleus. However, in ALS and FTLD patients with TDP-43-positive cytoplasmic inclusions, the protein is abnormally phosphorylated, ubiquitinated and truncated. This results in the accumulation of an B25-kDa C-terminal fragment (CTF25), in addition to other minor CTFs and the full-length TDP-43, in cytoplasmic aggregates. CTFs are hallmarks of forms of disease whose pathology is associated exclusively with abnormalities in TDP-43 and are observed in patients with not only ALS and FTLD but also Alzheimer's disease 5 . Amino-terminal (N-terminal) analysis of CTFs obtained from brain autopsies of patients with FTLD has resulted in the identification of three cleavage sites, Arg208, Asp219 and Asp247, which give rise to CTFs 6,7 . However, the expected sizes of the resulting CTFs are less than 25 kDa, which suggests that CTF25 is probably cleaved at a different position.TDP-43 is a widely expressed 414-amino acid (a.a.) protein comprised of two RNA recognition motifs (RRM1 at a.a. 106-176 and RRM2 at a.a. 191-262) and the GRD 8,9 . The chronic stabilization...

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Section: Discussionmentioning

confidence: 99%

The cleavage pattern of TDP-43 determines its rate of clearance and cytotoxicity

et al. 2015

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“…As mentioned above, GRP78 can sequester caspases and pro-apoptotic proteins, so GRP78 knockdown may release these proteins and enhance apoptotic signalling. In addition, EnR stress-induced signalling to apoptosis via CASPASE-4/12 [94,95] or the IRE1 -JNK pathway may be important. GRP78 knockdown is also known to induce apoptosis by blocking AKT activation in colon, PTEN-null leukaemia and prostate cancer cell lines [88,96,97].…”

Section: Discussionmentioning

confidence: 99%

Modelling the effect of GRP78 on anti-oestrogen sensitivity and resistance in breast cancer

et al. 2013

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One contribution of 11 to a Theme Issue 'Integrated cancer biology models'. Understanding the origins of resistance to anti-oestrogen drugs is of critical importance to many breast cancer patients. Recent experiments show that knockdown of GRP78, a key gene in the unfolded protein response (UPR), can re-sensitize resistant cells to anti-oestrogens, and overexpression of GRP78 in sensitive cells can cause them to become resistant. These results appear to arise from the operation and interaction of three cellular systems: the UPR, autophagy and apoptosis. To determine whether our current mechanistic understanding of these systems is sufficient to explain the experimental results, we built a mathematical model of the three systems and their interactions. We show that the model is capable of reproducing previously published experimental results and some new data gathered specifically for this paper. The model provides us with a tool to better understand the interactions that bring about anti-oestrogen resistance and the effects of GRP78 on both sensitive and resistant breast cancer cells.

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“…When PERK, ATF6 and IRE1 are active, they up-regulate the C/EBP homologous protein transcription factor (CHOP) expression. CHOP regulates apoptosis-related gene expression and induces cell apoptosis (26). ers-mediated apoptosis through the JnK or caspase-4 pathways have also been reported (27)(28)(29).…”

Section: Introductionmentioning

confidence: 97%

Involvement of endoplasmic reticulum stress in adenosine-induced human hepatoma HepG2 cell apoptosis

Ye²,

Huang³

et al. 2011

Oncol Rep

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Abstract. endoplasmic reticulum stress (ers)-mediated cell apoptosis has been implicated in the development of multiple diseases such as cancer, neurodegenerative diseases and ischemic reperfusion damage. previous studies have demonstrated the adenosine-induced apoptosis in several tumor cell lines. However, the role of ers in adenosine-induced human hepatoma Hepg2 cell apoptosis remains unclear. the present study was designed to determine whether ers is involved in adenosine-induced Hepg2 cell apoptosis. the Mtt assay was used to determine proliferation, and DApI staining of cell nuclei was performed to determine cell apoptosis. the translocation of cHop and caspase-3 was observed by immunofluorescence analysis, and the protein expression of CHOP, caspase-4 and caspase-3 was detected by Western blotting. the Mtt assay demonstrated that adenosine inhibited Hepg2 cell proliferation in a dose-dependent manner. DApI staining of cell nuclei and cell cycle analysis verified cell apoptosis. The immunofluorescence assay demonstrated that adenosine induced the translocation of cHop and of caspase-3 from the cytoplasm to the nucleus. Western blotting confirmed that cHop, caspase-4 and caspase-3 were up-regulated in Hepg2 cells after treatment with adenosine. However, JnK protein expression was not altered. These results show that ERS is involved in the adenosine-induced Hepg2 cell apoptosis.

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Endoplasmic reticulum stress-induced caspase-4 activation mediates apoptosis and neurodegeneration in INCL

Cited by 134 publications

References 30 publications

The cleavage pattern of TDP-43 determines its rate of clearance and cytotoxicity

The cleavage pattern of TDP-43 determines its rate of clearance and cytotoxicity

Modelling the effect of GRP78 on anti-oestrogen sensitivity and resistance in breast cancer

Involvement of endoplasmic reticulum stress in adenosine-induced human hepatoma HepG2 cell apoptosis

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