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MicroRNAs in apoptosis, autophagy and necroptosis.

Su Z, Yang Z, Xu Y, Chen Y, Yu Q - Oncotarget (2015)

Bottom Line: Numerous miRNAs regulate programmed cell death including apoptosis, autophagy and necroptosis.We summarize how miRNAs regulate apoptotic, autophagic and necroptotic pathways and cancer progression.We also discuss how miRNAs link different types of cell death.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Biology, Medical School, Southeast University, Nanjing, Jiangsu 210009, China.

ABSTRACT
MicroRNAs (miRNAs) are endogenous 22 nt non-coding RNAs that target mRNAs for cleavage or translational repression. Numerous miRNAs regulate programmed cell death including apoptosis, autophagy and necroptosis. We summarize how miRNAs regulate apoptotic, autophagic and necroptotic pathways and cancer progression. We also discuss how miRNAs link different types of cell death.

No MeSH data available.


Related in: MedlinePlus

miRNAs regulate necroptosisNecroptosis is triggered by TNF receptor superfamily members, TLRs, IFNRs, TCR, cellular metabolic and genotoxic stresses, and anticancer drugs. In TNF-α-induced necroptosis, the engagement of TNFR1 recruits Complex I (composed of TRADD, RIP1, TRAF2, CYLD, and cIAP1/2). In this complex, cIAP1 and cIAP2 ubiquitinate RIP1, whereas CYLD deubiquitinates RIP1. Polyubiquitinated RIP1 promotes NF-κB activation and prevents the formation of Complex II a (composed of caspase-8, FADD, RIP1) and Complex II b (composed of caspase-8, FADD, RIP1, RIP3, and MLKL), thus promoting cell survival and inhibiting apoptosis and necroptosis. RIP1 deubiquitination enables Complex II a formation, but whether the cell undergoes necroptosis is dependent on caspase-8 activity. Activated caspase-8 cleaves RIP1 and RIP3 and blocks necroptosis. However, if caspase-8 is inactivated by a pharmacological inhibitor (e.g., zVAD), an endogenous inhibitor (e.g., c-FLIPS) or genetic caspase-8 or FADD inhibition/deletion, it loses the capacity to cleave RIP1 and RIP3, leading to the trans-phosphorylation of these two kinases and the formation of a filamentous-like complex termed the necrosome. The RIP1-RIP3 necrosome subsequently recruits and activates MLKL and PGAM5. MLKL is phosphorylated by RIP3 and then forms a homotrimer that translocates to the plasma membrane, and this event leads to necrotic plasma membrane permeabilization. Upon necrosis induction, PGAM5S recruits and activates Drp1, which leads to mitochondrial fission, which is an early and necessary step for necrosis execution. The miRNAs involved in the regulation of key components of the necroptotic pathway are shown in the diagram in dark blue. TLRs, Toll-like receptors; TCR, T-cell receptor; IFNRs, interferon receptors; TNFR1, TNF-α receptor 1; TRADD, TNFR1-associated death domain protein; TRAF2, TNF receptor-associated factor 2; CYLD, cylindromatosis; cIAP1/2, cellular inhibitor of apoptosis 1/2; RIP1, receptor-interacting protein kinase 1, also referred to as RIPK1; IKK, IκB kinase; c-FLIPS, cellular FLICE-like inhibitory protein, short form. PGAM5, phosphoglycerate mutase 5; MLKL, mixed lineage kinase domain-like; Drp1, dynamin-related protein 1.
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Figure 4: miRNAs regulate necroptosisNecroptosis is triggered by TNF receptor superfamily members, TLRs, IFNRs, TCR, cellular metabolic and genotoxic stresses, and anticancer drugs. In TNF-α-induced necroptosis, the engagement of TNFR1 recruits Complex I (composed of TRADD, RIP1, TRAF2, CYLD, and cIAP1/2). In this complex, cIAP1 and cIAP2 ubiquitinate RIP1, whereas CYLD deubiquitinates RIP1. Polyubiquitinated RIP1 promotes NF-κB activation and prevents the formation of Complex II a (composed of caspase-8, FADD, RIP1) and Complex II b (composed of caspase-8, FADD, RIP1, RIP3, and MLKL), thus promoting cell survival and inhibiting apoptosis and necroptosis. RIP1 deubiquitination enables Complex II a formation, but whether the cell undergoes necroptosis is dependent on caspase-8 activity. Activated caspase-8 cleaves RIP1 and RIP3 and blocks necroptosis. However, if caspase-8 is inactivated by a pharmacological inhibitor (e.g., zVAD), an endogenous inhibitor (e.g., c-FLIPS) or genetic caspase-8 or FADD inhibition/deletion, it loses the capacity to cleave RIP1 and RIP3, leading to the trans-phosphorylation of these two kinases and the formation of a filamentous-like complex termed the necrosome. The RIP1-RIP3 necrosome subsequently recruits and activates MLKL and PGAM5. MLKL is phosphorylated by RIP3 and then forms a homotrimer that translocates to the plasma membrane, and this event leads to necrotic plasma membrane permeabilization. Upon necrosis induction, PGAM5S recruits and activates Drp1, which leads to mitochondrial fission, which is an early and necessary step for necrosis execution. The miRNAs involved in the regulation of key components of the necroptotic pathway are shown in the diagram in dark blue. TLRs, Toll-like receptors; TCR, T-cell receptor; IFNRs, interferon receptors; TNFR1, TNF-α receptor 1; TRADD, TNFR1-associated death domain protein; TRAF2, TNF receptor-associated factor 2; CYLD, cylindromatosis; cIAP1/2, cellular inhibitor of apoptosis 1/2; RIP1, receptor-interacting protein kinase 1, also referred to as RIPK1; IKK, IκB kinase; c-FLIPS, cellular FLICE-like inhibitory protein, short form. PGAM5, phosphoglycerate mutase 5; MLKL, mixed lineage kinase domain-like; Drp1, dynamin-related protein 1.

Mentions: Necrosis was traditionally thought to be an accidental and unregulated type of cell death. However, emerging evidence has shown that necrosis can be induced and regulated in a similar manner to apoptosis. Regulated necrosis is termed “programmed necrosis” or “necroptosis” to distinguish this process from necrosis induced by physical trauma [124]. Necroptosis can be induced by the engagement of the TNF receptor superfamily, T-cell receptor (TCR), interferon receptors (IFNRs), Toll-like receptors (TLRs), cellular metabolic and genotoxic stresses, and a number of anti-cancer agents [125]. Necroptosis can be pharmacologically inhibited using certain chemical compounds such as necrostatin-1 [126]. The formation of the “necrosome” by receptor-interacting protein kinase 1 (RIP1, also known as RIPK1) and RIP3 is the most critical event in necroptosis. Multiple stimuli and pathways that induce necroptosis ultimately converge at the RIP1-RIP3 necrosome. In TNF-α-induced necroptosis, the engagement of the TNF receptor recruits a series of proteins including TNFR1-associated death domain protein (TRADD), RIP1, TNF receptor-associated factor 2 (TRAF2), deubiquitinase cylindromatosis (CYLD), and cIAP1/2 to form a large complex termed Complex I. In this complex, cIAP1 and cIAP2 ubiquitinate RIP1 and prevent its entrance into Complex II a (composed of caspase-8, FADD, and RIP1) and Complex II b [composed of caspase-8, FADD, RIP1, RIP3, and mixed lineage kinase domain-like (MLKL)] [127], thus restricting subsequent apoptosis or necroptosis. Moreover, the poly-ubiquitination of RIP1 promotes NF-κB activation and cell survival. In contrast, CYLD is a deubiquitinating enzyme that is responsible for the removal of ubiquitin chains from RIP1 and that promotes the formation of ComplexIIa. Subsequently, caspase-8 cleaves RIP1 and RIP3, thus preventing their trans-phosphorylation and their phosphorylation of downstream necroptotic factors. However, if caspase-8 is inactivated by pharmacological inhibitors (e.g., zVAD), endogenous inhibitors (e.g., c-FLIPS), or genetic caspase-8 or FADD inhibition/deletion, it loses its capacity to cleave RIP1 and RIP3, leading to the phosphorylation of these two kinases and the formation of the filamentous-like RIP1-RIP3 complex, or the necrosome. The RIP1-RIP3 necrosome subsequently recruits and activates MLKL and phosphoglycerate mutase 5 (PGAM5), two critical downstream targets of RIP3 [128, 129]. During TNF-induced necroptosis, MLKL is phosphorylated by RIP3, forms a homotrimer via its amino-terminal coiled-coil domain, and translocates to the plasma membrane, and these events lead to necrotic plasma membrane permeabilization [130]. Upon necrosis induction, PGAM5S (a short form of PGAM5) recruits the mitochondrial fission factor dynamin-related protein 1 (Drp1) and activates its GTPase activity by dephosphorylating Drp1 at serine 637. Drp1 activation leads to mitochondrial fission, which is an early and necessary step for necrosis execution (shown in Figure 4) [131].


MicroRNAs in apoptosis, autophagy and necroptosis.

Su Z, Yang Z, Xu Y, Chen Y, Yu Q - Oncotarget (2015)

miRNAs regulate necroptosisNecroptosis is triggered by TNF receptor superfamily members, TLRs, IFNRs, TCR, cellular metabolic and genotoxic stresses, and anticancer drugs. In TNF-α-induced necroptosis, the engagement of TNFR1 recruits Complex I (composed of TRADD, RIP1, TRAF2, CYLD, and cIAP1/2). In this complex, cIAP1 and cIAP2 ubiquitinate RIP1, whereas CYLD deubiquitinates RIP1. Polyubiquitinated RIP1 promotes NF-κB activation and prevents the formation of Complex II a (composed of caspase-8, FADD, RIP1) and Complex II b (composed of caspase-8, FADD, RIP1, RIP3, and MLKL), thus promoting cell survival and inhibiting apoptosis and necroptosis. RIP1 deubiquitination enables Complex II a formation, but whether the cell undergoes necroptosis is dependent on caspase-8 activity. Activated caspase-8 cleaves RIP1 and RIP3 and blocks necroptosis. However, if caspase-8 is inactivated by a pharmacological inhibitor (e.g., zVAD), an endogenous inhibitor (e.g., c-FLIPS) or genetic caspase-8 or FADD inhibition/deletion, it loses the capacity to cleave RIP1 and RIP3, leading to the trans-phosphorylation of these two kinases and the formation of a filamentous-like complex termed the necrosome. The RIP1-RIP3 necrosome subsequently recruits and activates MLKL and PGAM5. MLKL is phosphorylated by RIP3 and then forms a homotrimer that translocates to the plasma membrane, and this event leads to necrotic plasma membrane permeabilization. Upon necrosis induction, PGAM5S recruits and activates Drp1, which leads to mitochondrial fission, which is an early and necessary step for necrosis execution. The miRNAs involved in the regulation of key components of the necroptotic pathway are shown in the diagram in dark blue. TLRs, Toll-like receptors; TCR, T-cell receptor; IFNRs, interferon receptors; TNFR1, TNF-α receptor 1; TRADD, TNFR1-associated death domain protein; TRAF2, TNF receptor-associated factor 2; CYLD, cylindromatosis; cIAP1/2, cellular inhibitor of apoptosis 1/2; RIP1, receptor-interacting protein kinase 1, also referred to as RIPK1; IKK, IκB kinase; c-FLIPS, cellular FLICE-like inhibitory protein, short form. PGAM5, phosphoglycerate mutase 5; MLKL, mixed lineage kinase domain-like; Drp1, dynamin-related protein 1.
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Figure 4: miRNAs regulate necroptosisNecroptosis is triggered by TNF receptor superfamily members, TLRs, IFNRs, TCR, cellular metabolic and genotoxic stresses, and anticancer drugs. In TNF-α-induced necroptosis, the engagement of TNFR1 recruits Complex I (composed of TRADD, RIP1, TRAF2, CYLD, and cIAP1/2). In this complex, cIAP1 and cIAP2 ubiquitinate RIP1, whereas CYLD deubiquitinates RIP1. Polyubiquitinated RIP1 promotes NF-κB activation and prevents the formation of Complex II a (composed of caspase-8, FADD, RIP1) and Complex II b (composed of caspase-8, FADD, RIP1, RIP3, and MLKL), thus promoting cell survival and inhibiting apoptosis and necroptosis. RIP1 deubiquitination enables Complex II a formation, but whether the cell undergoes necroptosis is dependent on caspase-8 activity. Activated caspase-8 cleaves RIP1 and RIP3 and blocks necroptosis. However, if caspase-8 is inactivated by a pharmacological inhibitor (e.g., zVAD), an endogenous inhibitor (e.g., c-FLIPS) or genetic caspase-8 or FADD inhibition/deletion, it loses the capacity to cleave RIP1 and RIP3, leading to the trans-phosphorylation of these two kinases and the formation of a filamentous-like complex termed the necrosome. The RIP1-RIP3 necrosome subsequently recruits and activates MLKL and PGAM5. MLKL is phosphorylated by RIP3 and then forms a homotrimer that translocates to the plasma membrane, and this event leads to necrotic plasma membrane permeabilization. Upon necrosis induction, PGAM5S recruits and activates Drp1, which leads to mitochondrial fission, which is an early and necessary step for necrosis execution. The miRNAs involved in the regulation of key components of the necroptotic pathway are shown in the diagram in dark blue. TLRs, Toll-like receptors; TCR, T-cell receptor; IFNRs, interferon receptors; TNFR1, TNF-α receptor 1; TRADD, TNFR1-associated death domain protein; TRAF2, TNF receptor-associated factor 2; CYLD, cylindromatosis; cIAP1/2, cellular inhibitor of apoptosis 1/2; RIP1, receptor-interacting protein kinase 1, also referred to as RIPK1; IKK, IκB kinase; c-FLIPS, cellular FLICE-like inhibitory protein, short form. PGAM5, phosphoglycerate mutase 5; MLKL, mixed lineage kinase domain-like; Drp1, dynamin-related protein 1.
Mentions: Necrosis was traditionally thought to be an accidental and unregulated type of cell death. However, emerging evidence has shown that necrosis can be induced and regulated in a similar manner to apoptosis. Regulated necrosis is termed “programmed necrosis” or “necroptosis” to distinguish this process from necrosis induced by physical trauma [124]. Necroptosis can be induced by the engagement of the TNF receptor superfamily, T-cell receptor (TCR), interferon receptors (IFNRs), Toll-like receptors (TLRs), cellular metabolic and genotoxic stresses, and a number of anti-cancer agents [125]. Necroptosis can be pharmacologically inhibited using certain chemical compounds such as necrostatin-1 [126]. The formation of the “necrosome” by receptor-interacting protein kinase 1 (RIP1, also known as RIPK1) and RIP3 is the most critical event in necroptosis. Multiple stimuli and pathways that induce necroptosis ultimately converge at the RIP1-RIP3 necrosome. In TNF-α-induced necroptosis, the engagement of the TNF receptor recruits a series of proteins including TNFR1-associated death domain protein (TRADD), RIP1, TNF receptor-associated factor 2 (TRAF2), deubiquitinase cylindromatosis (CYLD), and cIAP1/2 to form a large complex termed Complex I. In this complex, cIAP1 and cIAP2 ubiquitinate RIP1 and prevent its entrance into Complex II a (composed of caspase-8, FADD, and RIP1) and Complex II b [composed of caspase-8, FADD, RIP1, RIP3, and mixed lineage kinase domain-like (MLKL)] [127], thus restricting subsequent apoptosis or necroptosis. Moreover, the poly-ubiquitination of RIP1 promotes NF-κB activation and cell survival. In contrast, CYLD is a deubiquitinating enzyme that is responsible for the removal of ubiquitin chains from RIP1 and that promotes the formation of ComplexIIa. Subsequently, caspase-8 cleaves RIP1 and RIP3, thus preventing their trans-phosphorylation and their phosphorylation of downstream necroptotic factors. However, if caspase-8 is inactivated by pharmacological inhibitors (e.g., zVAD), endogenous inhibitors (e.g., c-FLIPS), or genetic caspase-8 or FADD inhibition/deletion, it loses its capacity to cleave RIP1 and RIP3, leading to the phosphorylation of these two kinases and the formation of the filamentous-like RIP1-RIP3 complex, or the necrosome. The RIP1-RIP3 necrosome subsequently recruits and activates MLKL and phosphoglycerate mutase 5 (PGAM5), two critical downstream targets of RIP3 [128, 129]. During TNF-induced necroptosis, MLKL is phosphorylated by RIP3, forms a homotrimer via its amino-terminal coiled-coil domain, and translocates to the plasma membrane, and these events lead to necrotic plasma membrane permeabilization [130]. Upon necrosis induction, PGAM5S (a short form of PGAM5) recruits the mitochondrial fission factor dynamin-related protein 1 (Drp1) and activates its GTPase activity by dephosphorylating Drp1 at serine 637. Drp1 activation leads to mitochondrial fission, which is an early and necessary step for necrosis execution (shown in Figure 4) [131].

Bottom Line: Numerous miRNAs regulate programmed cell death including apoptosis, autophagy and necroptosis.We summarize how miRNAs regulate apoptotic, autophagic and necroptotic pathways and cancer progression.We also discuss how miRNAs link different types of cell death.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Biology, Medical School, Southeast University, Nanjing, Jiangsu 210009, China.

ABSTRACT
MicroRNAs (miRNAs) are endogenous 22 nt non-coding RNAs that target mRNAs for cleavage or translational repression. Numerous miRNAs regulate programmed cell death including apoptosis, autophagy and necroptosis. We summarize how miRNAs regulate apoptotic, autophagic and necroptotic pathways and cancer progression. We also discuss how miRNAs link different types of cell death.

No MeSH data available.


Related in: MedlinePlus