The Role of Regulated Necrosis in Endocrine Diseases
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PERSPECTIVES system results in the typical morphological features such as rapid shrinking of the cell, The role of regulated necrosis nuclear condensation, DNA fragmentation, exposure of phosphatidylserine and a in endocrine diseases process known as membrane blebbing11,12. Phosphatidylserine exposure functions Wulf Tonnus , Alexia Belavgeni , Felix Beuschlein , Graeme Eisenhofer, as an ‘eat me’ signal to macrophages13–15. Martin Fassnacht , Matthias Kroiss , Nils P. Krone, Martin Reincke , Importantly, the plasma membrane remains intact in apoptotically dying cells, Stefan R. Bornstein and Andreas Linkermann a mechanism that prevents the release of Abstract | The death of endocrine cells is involved in type 1 diabetes mellitus, intracellular content to the interstitial and/or autoimmunity, adrenopause and hypogonadotropism. Insights from research on extracellular space. Therefore, apoptosis is immunologically silent. The detection basic cell death have revealed that most pathophysiologically important cell death of apoptosis has been misinterpreted for is necrotic in nature, whereas regular metabolism is maintained by apoptosis decades by the TdT-mediated dUTP-biotin programmes. Necrosis is defined as cell death by plasma membrane rupture, which nick end- labelling (TUNEL) method (BOx 1). allows the release of damage- associated molecular patterns that trigger an Mechanistically, extrinsic apoptosis immune response referred to as necroinflammation. Regulated necrosis comes in is mediated by death receptors such as different forms, such as necroptosis, pyroptosis and ferroptosis. In this Perspective, tumour necrosis factor receptor 1 (TNFR1) or the FAS receptor (also known as with a focus on the endocrine environment, we introduce these cell death CD95)16. To kill a cell through a TNFR1 pathways and discuss the specific consequences of regulated necrosis. Given that signal, upon binding of the ligand TNF, clinical trials of necrostatins for the treatment of autoimmune conditions have the TNFR1 signalling complex dissociates already been initiated, we highlight the therapeutic potential of such novel from the plasma membrane. Within the therapeutic approaches that, in our opinion, should be tested in endocrine cytosol, the FAS-associated death domain protein (FADD)- bound initiator caspase 8 disorders in the future. is recruited to the complex and interacts with receptor- interacting protein kinase 1 Endocrine glands control the human of endocrine disorders7,8, including septic (RIPK1)17,18. In the case of TNFR1, body’s metabolism, vital functions, mental adrenal dysfunction, autoimmune diseases however, the default signal to activate the and physical adaptation to stress, and such as type 1 diabetes mellitus (T1DM)9 transcription factor NF-κB is maintained the capacity to reproduce. Regulated cell and endocrine malignancies. Both the through the recruitment of kinases (IKKε necrosis and cell proliferation define prevention of cell death by rescuing cells and TBK1) through linear polyubiquitin endocrine tissue development and that otherwise succumb to necrosis (as is chains on RIPK1 (REF.19) and does not homeostasis, as well as its capacity to the case in T1DM)9 and the induction of result in cell death. Mechanistically, TBK1 adapt to stress and to prevent tumour necrosis in endocrine cancers (such as with phosphorylates RIPK1 and thereby inhibits formation. The term regulated cell death adrenocortical carcinomas)10 might lead its autophosphorylation-induced activation, was used mostly synonymously with to therapeutic benefits. This Perspective which is required for cell death. However, apoptosis until 15 years ago. However, our therefore aims to summarize the existing upon activation of caspase 8, RIPK1 activity understanding of necrosis as a regulated data on the newly characterized cell death is prevented by proteolytic cleavage of RIPK1 process has dramatically expanded since pathways in endocrine disorders while by caspase 8 (REF.20). The proteolytically then. In the past 15 years, we have begun focusing on unanswered questions. We also active caspase 8 also cleaves the effectors to understand the details of necroptosis, discuss the need to revisit the literature caspase 3, caspase 6 and caspase 7 (REF.21), pyroptosis and ferroptosis1. Necrosis that was published before the identification which mediate the apoptotic cellular not only causes organ dysfunction but of necroptosis, pyroptosis and ferroptosis phenotype. As caspase 8 also controls the also results in an inflammatory response and reinterpret it in the light of the current activation of the pyroptosis pathway22, driven by damage-associated molecular understanding to highlight the possibility of it must be interpreted as the master regulator patterns (DAMPs), which is referred to as therapeutic interventions. of death receptor-mediated cell death. necroinflammation2,3. The control of extrinsic apoptosis and Studies have shown that the three The types of regulated cell death necroptosis (which is discussed in the next pathways of regulated necrosis, namely Apoptosis: well defined and well tolerated by section) by post- translational modification is necroptosis, pyroptosis and ferroptosis, can the immune system. Apoptosis (Fig. 1a) is the reviewed in more detail elsewhere23–25. be therapeutically targeted4–6. Accumulating default cell death pathway for homeostasis By contrast, loss of the mitochondrial data suggest that necroinflammation is of and cellular turnover during physiological outer membrane potential and the central relevance in the pathophysiology metabolism11,12. The caspase-controlled recruitment of BAX and BAK to the outer NATURE REVIEWS | ENDOCRINOLOGY VOLUME 17 | AUGUST 2021 | 497 0123456789();: PERSPECTIVES a Apoptosis Apoptotic vesicle b Necroptosis RHIM domain TNFR1 Exposure of TRAILR phosphatidylserine TLR TRADD P FAS casp8 TRIF TRADD M1 Ub P P RIPK1 NEMO P chain RIPK3 TANK P RIPK1 P P K63 FADD RIPK3 TAK1 OTULIN IKKε RIPK1 NEMO casp8 MK2 TBK1 TANK P IKKε Loss SHARPIN DD TBK1 of Ub Viral DNA HOIP casp8 c-FLIP chains CYLD BAK and/or RNA HSP90 A20 HOIL1 BAX cIAP1 P RIPK3 P MOMP P P cIAP2 LUBAC BID RIPK3 complex tBID P P RIPK3 MLKL P ? Cytochrome c P RIPK3 P SMAC CDC37 Extrinsic ZBP1 MLKL P Lysosome APAF1 Necrosome P XIAP RIPK3 P Nucleus RIPK3 MLKL P Degradation casp3 Intrinsic MLKL P Effector casp6 casp9 MLKL P caspases P casp7 P P MLKL P P P P MLKL P MLKL P MLKL Flotilin MLKL P MLKL MLKL P MLKL MLKL MLKL MLKL Apoptosis ESCRT-III MLKL P • Membrane MLKL P rupture MLKL P • DAMP release MLKL P MLKL P P Cell death MLKL Survival MLKL P MLKL P c Pyroptosis d Ferroptosis K+ efflux Glutamate Bacterium Potassium DAMPs System x – channel c Peroxisome SLC3A2 SLC7A11 Cystine casp8 ? ASC • 3 × Glutamate Cysteine ER • 4×ATP H O • 5 × Glycogen 2 2 NLRP3 POR and/or CYB5R1 NADPH 2 × GSH Casp1/11 Inflammasome GPX4 AA FA NADP+ GSR GSSG ASC c-FLIP 2+ ACSL4 Fe +H2O2 AA-CoA FA-CoA 2 Acetyl-CoA Fe3+ + HO + HO˙ casp1 casp8 III IV casp11 II Pro-IL-1β HMG-CoA PL-OOH I Pro-IL-18 HMGCR PL-OH GSDMD casp3 Mevalonate OXPHOS IL-1β Co-Q10 PE-AA-OOH C IL-18 Mevalonate pathway N FPP Prenylated Prominin 2 Lipid Ferritin proteins peroxidation MVB N-terminal Squalene Fe2+ GSDMD RTA Cholesterol Ferritin ESCRT-III • Membrane rupture FSP1 TSG101 and/or 2+ • DAMP release DAMP Ca AIFM2 release N ESCRT-III Ferritin Inflammation TSG101 N Cell death Cell death Membrane repair Ferroptosis N Survival mechanism sensitivity 498 | AUGUST 2021 | VOLUME 17 www.nature.com/nrendo 0123456789();: PERSPECTIVES ◀ Fig. 1 | Regulated cell death pathways at a glance. Apoptosis represents a non-inflammatory path- SHARPIN, HOIP and HOIL1, generates way that is mediated by caspases (part a). Two distinct signalling pathways of apoptosis, extrinsic and linear polyubiquitin chains59–61. The intrinsic apoptosis, have been characterized. While apoptosis depends on the activation of caspases, polyubiquitin chains are disassembled by necroptosis is mediated by kinases (part b). Dependent on its RHIM domain, RIPK3 forms an amyloid- the deubiquitinases (DUBs) referred to as like structure referred to as the necrosome, the central signalling platform of necroptosis. Therein, (REFS62,63) 20,64–67 RIPK3 phosphorylates the pseudokinase MLKL. By unknown mechanisms, the phosphorylated form of A20 and CYLD in the case of 68–70 MLKL (pMLKL) triggers plasma membrane rupture, a process that was demonstrated to be counter- K63 linkages and as OTULIN in the case acted by the membrane repair ESCRT- III complex. In contrast to apoptosis and necroptosis, inflam- of linear chains. It is this subtle equilibrium of masomes are involved in the initiation of cell death by pyroptosis (part c). The activation of caspases post- translational modification that (1, 4, 11) in inflammasomes results in the cleavage of pro- IL-1β, pro- IL-18 and gasdermin D (GSDMD). determines if the kinases IKKε and TBK1 Finally, and without any clear connection to apoptosis, necroptosis and pyroptosis, ferroptosis is a are recruited into the complex and prevent 71 failsafe rather than a typical cell death pathway (part d). In cellular homeostasis, H2O2 concentrations cell death signalling either by apoptosis or of iron-catalysed and Fenton reactions are limited by diverse cellular anti-redox systems. Glutathione by necroptosis19. In addition, the sensitivity to peroxidase 4 (GPX4) prevents lipid peroxidation that otherwise leads to plasma membrane rupture by necroptosis is further regulated on different unknown mechanisms. By contrast, the oxidoreductase FSP1