PELI1 Selectively Targets Kinase-Active RIP3 for Ubiquitylation-Dependent Proteasomal Degradation

Choi, Seung Won; Park, Han Hee; Kim, Soyeon; Chung, Jee Min; Noh, Han-Jin; Kim, Sue Kyung; Song, Hyun Kyu; Lee, Chang Woo; Morgan, Michael J.; Kang, Ho Chul; Kim, You Sun

doi:10.1016/j.molcel.2018.05.016

Cited by 84 publications

(95 citation statements)

References 56 publications

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“…MLKL is a key effector of necroptosis and upon activation by phosphorylated RIP1, RIP3 will recruit and phosphorylate MLKL to execute necroptosis 30 . During this process, MLKL forms an oligomer and translocates to the plasma membrane to cause membrane rupture.…”

Section: Discussionmentioning

confidence: 99%

Reduction in MLKL-mediated endosomal trafficking enhances the TRAIL-DR4/5 signal to increase cancer cell death

Park

et al. 2020

Cell Death Dis

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Mixed lineage kinase domain-like (MLKL) is an essential molecule of necroptosis, a cell death process that is initiated by direct disruption of the plasma membrane. During necroptosis, MLKL is phosphorylated by receptor interacting protein kinase-3 (RIPK3 or RIP3), and then translocates to the plasma membrane to disrupt membrane integrity. Recent data suggest that MLKL also has a RIP3-indendent function in the generation of intraluminal and extracellular vesicles (EVs), as well as in myelin sheath breakdown when promoting sciatic nerve regeneration. Here we show that depletion of MLKL enhances TRAIL-induced cell death in a RIP3-independent manner. Depletion of MLKL leads to prolonged cytotoxic signals that increase TRAIL-induced cell death. Initially, TRAIL binds to DR5 at the cell surface and is endocytosed at similar rates in MLKL-expressing and MLKL-depleted cells, eventual degradation of intracellular TRAIL by the lysosome is delayed in MLKL-depleted cells, corresponding with prolonged/enhanced intracellular signals such as p-ERK and p-p38 in these cells. Colocalization of TRAIL with the marker of early endosomes, EEA1 suggests that TRAIL is accumulated in early endosomes in MLKL-depleted cells compared to MLKL-expressing cells. This indicates that depletion of MLKL reduces receptor-ligand endosomal trafficking leading to increased TRAIL-cytotoxicity. An MLKL mutant that compromises its necroptotic function and its function in the generation of EVs was sufficient to rescue MLKL deficiency, suggesting that the N-terminal structural elements necessary for these functions are not required for the function of MLKL in the intracellular trafficking associated with regulating death receptor cytotoxicity. A reduction in MLKL expression in cancer cells would therefore be expected to result in enhanced TRAIL-induced therapeutic efficacy.

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Section: Discussionmentioning

confidence: 99%

Reduction in MLKL-mediated endosomal trafficking enhances the TRAIL-DR4/5 signal to increase cancer cell death

Park

et al. 2020

Cell Death Dis

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“…We and others have previously demonstrated that Peli1 was an E3 ubiquitin ligase mediating protein activation or stability through adding the poly-ubiquitin chains to the substrates [ 26 , 37 – 39 ]. The increased C/EBPβ protein levels in Peli1 -knockdown microglial cells promoted us to investigate whether Peli1 directly regulated the ubiquitination of this transcription factor.…”

Section: Resultsmentioning

confidence: 99%

Peli1 impairs microglial Aβ phagocytosis through promoting C/EBPβ degradation

Pietronigro

et al. 2020

PLoS Biol

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Amyloid-β (Aβ) accumulation in the brain is a hallmark of Alzheimer's disease (AD) pathology. However, the molecular mechanism controlling microglial Aβ phagocytosis is poorly understood. Here we found that the E3 ubiquitin ligase Pellino 1 (Peli1) is induced in the microglia of AD-like five familial AD (5×FAD) mice, whose phagocytic efficiency for Aβ was then impaired, and therefore Peli1 depletion suppressed the Aβ deposition in the brains of 5×FAD mice. Mechanistic characterizations indicated that Peli1 directly targeted CCAAT/ enhancer-binding protein (C/EBP)β, a major transcription factor responsible for the transcription of scavenger receptor CD36. Peli1 functioned as a direct E3 ubiquitin ligase of C/EBPβ and mediated its ubiquitination-induced degradation. Consequently, loss of Peli1 increased the protein levels of C/EBPβ and the expression of CD36 and thus, promoted the phagocytic ability in microglial cells. Together, our findings established Peli1 as a critical regulator of microglial phagocytosis and highlighted the therapeutic potential by targeting Peli1 for the treatment of microglia-mediated neurological diseases.

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“…Thus, several checkpoint regulators may be necessary to block the uninhibited progress of necroptosis. Recently, several proteins modulating necroptosis have been reported [17][18][19][20][21][22][23][24][25][26][27]. These regulatory proteins are limited in the pre-necrosome complex step, which consists of the process before the formation of the RIPK1/RIPK3 complex.…”

Section: Discussionmentioning

confidence: 99%

“…In addition to RIPK1 modification, RIPK3 posttranslational modifications are crucial events in necroptosis. CHIP and Pellino 1 ubiquitinate and degrade RIPK3 protein levels in an ubiquitin-mediated lysosome- and proteasome-dependent manner, suppressing necroptosis [ 24 , 25 ]. A20 removes RIPK3 ubiquitination, which restricts necrosome complex formation [ 26 ].…”

Section: Introductionmentioning

confidence: 99%

Beclin 1 functions as a negative modulator of MLKL oligomerisation by integrating into the necrosome complex

et al. 2020

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Necroptosis is a form of regulated cell death caused by formation of the necrosome complex. However, the factors modulating this process and the systemic pathophysiological effects of necroptosis are yet to be understood. Here, we identified that Beclin 1 functions as an anti-necroptosis factor by being recruited into the necrosome complex upon treatment with TNFα, Smac mimetic, and pan-caspase inhibitor and by repressing MLKL oligomerisation, thus preventing the disruption of the plasma membrane. Cells ablated or knocked-out for Beclin 1 become sensitised to necroptosis in an autophagy-independent manner without affecting the necrosome formation itself. Interestingly, the recruitment of Beclin 1 into the necrosome complex is dependent on the activation and phosphorylation of MLKL. Biochemically, the coiled-coil domain (CCD) of Beclin 1 binds to the CCD of MLKL, which restrains the oligomerisation of phosphorylated MLKL. Finally, Beclin 1 depletion was found to promote necroptosis in leukaemia cells and enhance regression of xenografted-tumour upon treatment with Smac mimetics and caspase inhibitors. These results suggest that Beclin 1 functions as a negative regulator in the execution of necroptosis by suppressing MLKL oligomerisation.

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PELI1 Selectively Targets Kinase-Active RIP3 for Ubiquitylation-Dependent Proteasomal Degradation

Cited by 84 publications

References 56 publications

Reduction in MLKL-mediated endosomal trafficking enhances the TRAIL-DR4/5 signal to increase cancer cell death

Reduction in MLKL-mediated endosomal trafficking enhances the TRAIL-DR4/5 signal to increase cancer cell death

Peli1 impairs microglial Aβ phagocytosis through promoting C/EBPβ degradation

Beclin 1 functions as a negative modulator of MLKL oligomerisation by integrating into the necrosome complex

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