Caspase-mediated cleavage of the stacking protein GRASP65 is required for Golgi fragmentation during apoptosis

Lane, Jon D.; Lucocq, John M.; Pryde, James G.; Barr, Francis A.; Woodman, Philip; Allan, Viki; Lowe, Martin

doi:10.1083/jcb.200110007

Cited by 212 publications

(231 citation statements)

References 41 publications

(59 reference statements)

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“…A number of secretory pathway proteins are substrates for caspase cleavage, including BAP-31 in the ER (Ng et al, 1997), and golgin-160 (Mancini et al, 2000), giantin (Lowe et al, 2004), GRASP65 (Lane et al, 2002), and p115 (Chiu et al, 2002) at the Golgi. Besides contributing to organelle disassembly, cleavage of some of these proteins seems to be important for initiation of apoptosis.…”

Section: Discussionmentioning

confidence: 99%

“…Whereas elements of mitotic and apoptotic Golgi disassembly seem to have features in common (Sesso et al, 1999), apoptotic Golgi disassembly is irreversible and primarily depends on protein cleavage rather than phosphorylation. During apoptosis, caspases cleave proteins involved in Golgi structure and trafficking, including golgin-160 (Mancini et al, 2000), GM130 (Nozawa et al, 2002;Lowe et al, 2004), giantin (Lowe et al, 2004), GRASP65 (Lane et al, 2002), and p115 (Chiu et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

“…Caspase cleavage of the Golgi t-SNARE syntaxin-5 (Lowe et al, 2004) and Golgilocalized components of the dynein-dynactin motor complex (Lane et al, 2001) have been implicated in termination of membrane trafficking during apoptosis. Expression of caspase-resistant mutants of golgin-160, GRASP65, or p115 delays Golgi disassembly during apoptosis (Mancini et al, 2000;Chiu et al, 2002;Lane et al, 2002). Expression of a construct mimicking the C-terminal caspase-cleavage product of p115 causes Golgi fragmentation and induces apoptosis (Chiu et al, 2002).…”

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confidence: 99%

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Caspase-resistant Golgin-160 Disrupts Apoptosis Induced by Secretory Pathway Stress and Ligation of Death Receptors

Maag

Mancini

Rosen

et al. 2005

MBoC

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Golgin-160 is a coiled-coil protein on the cytoplasmic face of the Golgi complex that is cleaved by caspases during apoptosis. We assessed the sensitivity of cell lines stably expressing wild-type or caspase-resistant golgin-160 to several proapoptotic stimuli. Cells expressing a caspase-resistant mutant of golgin-160 were strikingly resistant to apoptosis induced by ligation of death receptors and by drugs that induce endoplasmic reticulum (ER) stress, including brefeldin-A, dithiothreitol, and thapsigargin. However, both cell lines responded similarly to other proapoptotic stimuli, including staurosporine, anisomycin, and etoposide. The caspase-resistant golgin-160 dominantly prevented cleavage of endogenous golgin-160 after ligation of death receptors or induction of ER stress, which could be explained by a failure of initiator caspase activation. The block in apoptosis in cells expressing caspase-resistant golgin-160 could not be bypassed by expression of potential caspase cleavage fragments of golgin-160, or by drug-induced disassembly of the Golgi complex. Our results suggest that some apoptotic signals (including those initiated by death receptors and ER stress) are sensed and integrated at Golgi membranes and that golgin-160 plays an important role in transduction of these signals. INTRODUCTIONThe Golgi complex is central to the regulation of membrane trafficking in eukaryotic cells. It is the primary site for sorting and processing of proteins undergoing both exocytosis and endocytosis (reviewed in Farquhar and Palade, 1998). Under normal conditions, the mammalian Golgi complex is a collection of stacks of cisternal membranes near the microtubule organizing center. Proteins traversing the secretory pathway enter the Golgi at the cis face, are processed as they pass through the Golgi stacks, and are sorted at the trans face into vesicles bound for their intended destinations. The trans-Golgi is also important in sorting proteins being endocytosed or cycling between the plasma membrane and intracellular membrane compartments. This affords the Golgi extensive communication with the rest of the cell and its surroundings, placing it in a prime position to sense and integrate information about the state of the cell and its environment.The structure of the Golgi is highly dynamic, allowing reversible disassembly during mitosis. Key secretory pathway proteins are phosphorylated in a cell cycle-dependent manner to stop membrane trafficking and disassemble the Golgi (reviewed in Rabouille and Jokitalo, 2003). This rearrangement from a single perinuclear organelle to dispersed vesiculated compartments is thought to ensure partitioning of the Golgi complex into both daughter cells during cytokinesis. When Golgi disassembly is prevented by addition of antibodies to Golgi reassembly and stacking protein of 65 kDa (GRASP65), cells complete S phase, but they are unable to enter mitosis. This mitotic block can be bypassed by disassembling the Golgi with drugs (Sutterlin et al., 2002). Once mitosis is complete, the Golgi...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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confidence: 99%

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Caspase-resistant Golgin-160 Disrupts Apoptosis Induced by Secretory Pathway Stress and Ligation of Death Receptors

Maag

Mancini

Rosen

et al. 2005

MBoC

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“…It is of interest to note that in apoptotic cells, the NH 2 -terminal head domain of GCP170 was cleaved by caspases, whereas a mutant form of GCP170 lacking the caspase-2 cleavage site appeared to delay the Golgi fragmentation (26). In addition, Lane et al (49) most recently reported that the stacking protein GRASP65 was also cleaved by caspase-3 during apoptosis, resulting in Golgi fragmentation. These observations strongly suggest that GCP170 and GRASP65 of the golgin family are indeed required for the assembly and maintenance of the Golgi structure.…”

Section: Discussionmentioning

confidence: 99%

Identification and Characterization of GCP16, a Novel Acylated Golgi Protein That Interacts with GCP170

Ohta

Misumi

Sohda

et al. 2003

Journal of Biological Chemistry

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GCP170, a member of the golgin family associated with the cytoplasmic face of the Golgi membrane, was found to have a Golgi localization signal at the NH 2 -terminal region (positions 137-237). Using this domain as bait in the yeast two-hybrid screening system, we identified a novel protein that interacted with GCP170. The 2.0-kilobase mRNA encoding a 137-amino acid protein of 16 kDa designated GCP16 was ubiquitously expressed. Immunofluorescence microscopy showed that GCP16 was co-localized with GCP170 and giantin in the Golgi region. Despite the absence of a hydrophobic domain sufficient for participating in membrane localization, GCP16 was found to be tightly associated with membranes like an integral membrane protein. 69 and Cys 72 , accounting for its tight association with the membrane. A mutant without potential acylation sites (C69A/C72A) was no longer localized to the Golgi, indicating that the acylation is prerequisite for the Golgi localization of GCP16. Although the mutant GCP16, even when overexpressed, had no effect on protein transport, overexpression of the wild type GCP16 caused an inhibitory effect on protein transport from the Golgi to the cell surface. Taken together, these results indicate that GCP16 is the acylated membrane protein, associated with GCP170, and possibly involved in vesicular transport from the Golgi to the cell surface. Labeling experiments with [ 3 H]palmitic acid and mutational analysis demonstrated that GCP16 was acylated at Cys

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“…Along with this possibility, it has been demonstrated that stress in ER can induce apoptosis (Welihinda et al 1999), at least through Ca 2 ϩ release and the activation of caspase-12 (Nakagawa et al 2000). In addi- tion, Golgi disruption has been described in apoptosisinduced HeLa cells through activation of caspase-2 (Mancini et al 2000) and caspase-3, as recently reported (Lane et al 2002). We conclude that Golgi modifications found in a rat OA-induced model matches cartilage damage progression and we speculate that they might be related to chondrocyte death by apoptosis, first increasing synthesis and finally implicated in chondrocytes fragmentation.…”

Section: Discussionmentioning

confidence: 78%

Modifications of Golgi Complex in Chondrocytes from Osteoarthrotic (OA) Rat Cartilage

Kourí

Rojas

Pérez

et al. 2002

J Histochem Cytochem.

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S U M M A R YThe status of the Golgi complex in normal vs osteoarthrotic (OA) cartilage has not yet been studied. A monoclonal antibody, MAb 58-K-9, allowed scoring of Golgi labeling intensity. In addition, ultrastructural assessment enabled us to focus on the distribution and relation between the endoplasmic reticulum (ER) and Golgi membranes. The study was performed in both normal and partially menisectomized OA-induced rat cartilage 20 and 45 days after surgery. Comparing Golgi immunolabeling intensities (mean Ϯ SEM) revealed a highly significant difference between normal (9.98 Ϯ 1.25), 20-day (2.49 Ϯ 0.34), and 45-day (0.82 Ϯ 0.22) cartilage. Moreover, chondrocytes from normal cartilage displayed 71.18% of labeling intensity in contrast to OA cartilage, in which chondrocyte labeling intensities were 24.95% (20 days) and 8.11% (45 days). OA chondrocytes appeared to display an overall reduction in Golgi labeling intensity, suggesting disruption of this organelle as the OA damage progressed. Interestingly, many 20-day OA-induced chondrocytes exhibited bubble-like Golgi immunolabeling compartmentalizing the cytoplasm, concomitant with putative apoptotic nuclear changes. At the same time, OA chondrocytes with a typical ultrastructural apoptotic pattern revealed a prominent ER gathered together with Golgi vesicles and saccules, also appearing to compartmentalize chondrocyte cytoplasm. We speculate about the role of Golgi modifications and apoptosis in OA pathogenesis.

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Caspase-mediated cleavage of the stacking protein GRASP65 is required for Golgi fragmentation during apoptosis

Cited by 212 publications

References 41 publications

Caspase-resistant Golgin-160 Disrupts Apoptosis Induced by Secretory Pathway Stress and Ligation of Death Receptors

Caspase-resistant Golgin-160 Disrupts Apoptosis Induced by Secretory Pathway Stress and Ligation of Death Receptors

Identification and Characterization of GCP16, a Novel Acylated Golgi Protein That Interacts with GCP170

Modifications of Golgi Complex in Chondrocytes from Osteoarthrotic (OA) Rat Cartilage

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