Phenotypic differences between mice deficient in XIAP and SAP, two factors targeted in X-linked lymphoproliferative syndrome (XLP)

Mutations in the X-linked inhibitor of apoptosis (XIAP) have recently been identified in patients with the rare genetic disease, X-linked lymphoproliferative syndrome (XLP), which was previously thought to be solely attributable to mutations in a distinct gene, SAP. To further understand the roles of these two factors in the pathogenesis of XLP, we have compared mice deficient in Xiap with known phenotypes of Sap-null mice. We show here that in contrast to Sap-deficient mice, animals lacking Xiap have apparently normal NKT cell development and no apparent defect in humoral responses to T cell-dependent antigens. However, Xiap-deficient cells were more susceptible to death upon infection with the murine herpesvirus MHV-68 and gave rise to more infectious virus. These differences could be rescued by restoration of XIAP. These data provide insight into the differing roles of XIAP and SAP in the pathogenesis of XLP.     

Loss-of-Function Ferrochelatase and Gain-of-Function Erythroid-Specific 5-Aminolevulinate Synthase Mutations Causing Erythropoietic Protoporphyria and X-Linked Protoporphyria in North American Patients Reveal Novel Mutations and a High Prevalence of X-Linked Protoporphyria

Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) are inborn errors of heme biosynthesis with the same phenotype but resulting from autosomal recessive loss-of-function mutations in the ferrochelatase (FECH) gene and gain-of-function mutations in the X-linked erythroid-specific 5-aminolevulinate synthase (ALAS2) gene, respectively. The EPP phenotype is characterized by acute, painful, cutaneous photosensitivity and elevated erythrocyte protoporphyrin levels. We report the FECH and ALAS2 mutations in 155 unrelated North American patients with the EPP phenotype. FECH sequencing and dosage analyses identified 140 patients with EPP: 134 with one loss-of-function allele and the common IVS3-48T>C low expression allele, three with two loss-of-function mutations and three with one loss-of-function mutation and two low expression alleles. There were 48 previously reported and 23 novel FECH mutations. The remaining 15 probands had ALAS2 gain-of-function mutations causing XLP: 13 with the previously reported deletion, c.1706_1709delAGTG, and two with novel mutations, c.1734delG and c.1642C>T(p.Q548X). Notably, XLP represented ~10% of EPP phenotype patients in North America, two to five times more than in Western Europe. XLP males had twofold higher erythrocyte protoporphyrin levels than EPP patients, predisposing to more severe photosensitivity and liver disease. Identification of XLP patients permits accurate diagnosis and counseling of at-risk relatives and asymptomatic heterozygotes.     

Bax/Bak-dependent,Drp1-independent Targeting of X-linked Inhibitor of Apoptosis Protein (XIAP) into Inner Mitochondrial Compartments Counteracts Smac/DIABLO-dependent Effector Caspase Activation

Efficient apoptosis requires Bax/Bak-mediated mitochondrial outer membrane permeabilization (MOMP), which releases death-promoting proteins cytochrome c and Smac to the cytosol, which activate apoptosis and inhibit X-linked inhibitor of apoptosis protein (XIAP) suppression of executioner caspases, respectively. We recently identified that in response to Bcl-2 homology domain 3 (BH3)-only proteins and mitochondrial depolarization, XIAP can permeabilize and enter mitochondria. Consequently, XIAP E3 ligase activity recruits endolysosomes into mitochondria, resulting in Smac degradation. Here, we explored mitochondrial XIAP action within the intrinsic apoptosis signaling pathway. Mechanistically, we demonstrate that mitochondrial XIAP entry requires Bax or Bak and is antagonized by pro-survival Bcl-2 proteins. Moreover, intramitochondrial Smac degradation by XIAP occurs independently of Drp1-regulated cytochrome c release. Importantly, mitochondrial XIAP actions are activated cell-intrinsically by typical apoptosis inducers TNF and staurosporine, and XIAP overexpression reduces the lag time between the administration of an apoptotic stimuli and the onset of mitochondrial permeabilization. To elucidate the role of mitochondrial XIAP action during apoptosis, we integrated our findings within a mathematical model of intrinsic apoptosis signaling. Simulations suggest that moderate increases of XIAP, combined with mitochondrial XIAP preconditioning, would reduce MOMP signaling. To test this scenario, we pre-activated XIAP at mitochondria via mitochondrial depolarization or by artificially targeting XIAP to the intermembrane space. Both approaches resulted in suppression of TNF-mediated caspase activation. Taken together, we propose that XIAP enters mitochondria through a novel mode of mitochondrial permeabilization and through Smac degradation can compete with canonical MOMP to act as an anti-apoptotic tuning mechanism, reducing the mitochondrial contribution to the cellular apoptosis capacity.     

Lack of X-linked inhibitor of apoptosis protein leads to increased apoptosis and tissue loss following neonatal brain injury

Neurological deficits caused by H-I (hypoxia-ischaemia) to the perinatal brain are often severely debilitating and lead to motor impairment, intellectual disability and seizures. Perinatal brain injury is distinct from adult brain injury in that the developing brain is undergoing the normal process of neuronal elimination by apoptotic cell death and thus the apoptotic machinery is more easily engaged and activated in response to injury. Thus cell death in response to neonatal H-I brain injury is partially due to mitochondrial dysfunction and activation of the apoptosome and caspase 3. An important regulator of the apoptotic response following mitochondrial dysfunction is XIAP (X-linked inhibitor of apoptosis protein). XIAP inhibits apoptosis at the level of caspase 9 and caspase 3 activation, and lack of XIAP in vitro has been shown to lead to increased apoptotic cell death. In the present study we show that mice lacking the gene encoding the XIAP protein have an exacerbated response to neonatal H-I injury as measured by tissue loss at 7 days following the injury. In addition, when the XIAP-deficient mice were studied at 24 h post-H-I we found that the increase in injury correlates with an increased apoptotic response in the XIAP-deficient mice and also with brain imaging changes in T2-weighted magnetic resonance imaging and apparent diffusion coefficient that correspond to the location of apoptotic cell death. These results identify a critical role of XIAP in regulating neuronal apoptosis in vivo and demonstrate the enhanced vulnerability of neurons to injury in the absence of XIAP in the developing brain.     

MicroRNA-513a-5p mediates TNF-α and LPS induced apoptosis via downregulation of X-linked inhibitor of apoptotic protein in endothelial cells

MicroRNAs (miRNAs) are endogenous non-coding small RNAs that have emerged as one of the central players of gene expression regulation. Endothelial cell apoptosis plays a fundamental role in the development of atherosclerosis. This study was designed to determine the effect of miR-513a-5p on apoptosis of human umbilical vein endothelial cells (HUVECs). HUVECs were treated with tumour necrosis factor-α (TNF-α) and lipopolysaccharide (LPS) and miR-513a-5p expression levels were determined. MiR-513a-5p target gene indentification, validation, and signalling pathways were investigated. Treatment of HUVECs with TNF-α and LPS up-regulated miR-513a-5p expressions more than 2-fold compared to control (P < 0.05). Inhibition of miR-513a-5p by antisense (AS) miR-513a-5p reversed TNF-α and LPS induced apoptosis (P < 0.01). Transfection of HUVECs with miR-513a-5p mimics also induced apoptosis (P < 0.01). Treatment of HUVECs with TNF-α and LPS attenuated X-linked inhibitor of apoptosis (XIAP) while increased caspase-3 expression, poly ADP-ribose polymerase (PARP) cleavage, and p53 expression. These effects were reversed by inhibition of miR-513a-5p. Of those miR-513a-5p candidate target genes, we identified and validated XIAP as a miR-513a-5p target gene. Targeting of the XIAP 3′-untranslated region by miR-513a-5p using luciferase reporter assay resulted in attenuated luciferase activity. Transfection of HUVECs with AS miR-513a-5p increased XIAP protein expression while miR-513a-5p mimics attenuated XIAP expression. These results together suggest that miR-513a-5p mediates TNF-α and LPS induced apoptosis via downregulation of XIAP in HUVECs.     

Clinical and laboratory characteristics of hemophagocytic lymphohistiocytosis induced by Leishmania infantum infection

BackgroundVisceral leishmaniasis (VL) could progress to secondary hemophagocytic lymphohistiocytosis (HLH), which is a rare but life-threatening condition with poor prognosis. So far, the clinical and laboratory characteristics of VL associated HLH have not been well elucidated.Method and findingsIn this study, we retrospectively analyzed the clinical and laboratory profiles between 17 patients with VL associated HLH and 27 patients with VL alone admitted at the Beijing Friendship Hospital, Capital Medical University from May 2016 to March 2021. In addition to the identification of Leishmania infection, hemophagocytosis was identified in bone marrow in the most cases of VL associated HLH (15/17). The patients with VL associated HLH had higher chances of bleeding, hepatomegaly, thrombocytopenia, hypertriglyceridemia, hyperferritinemia, hypofibrinogenemia, elevated secretion of soluble IL-2 receptor or lower NK cell activity compared to patients with VL only. Furthermore, patients with VL associated HLH had higher inflammation status associated with higher levels of Th1 (TNF-α, IFN-γ, IL-1beta, IL-6, IL-8, IL-12p70), Th2 (IL-4) and Th17 cytokines (IL-17, IL-23) in the peripheral blood, and higher parasite load (qPCR and parasite culture). All 27 VL cases were totally recovered after being treated with Sodium Stibogluconate, five of the 17 patients with VL associated HLH died even after timely treatment with anti-parasite and immunosuppressive chemotherapy.ConclusionWithout appropriate treatment, visceral leishmaniosis could develop to secondary HLH. The parasite culturing and qPCR detection of bone marrow samples facilitates the diagnosis of VL associated HLH in addition to other findings of HLH. Prompt treatment with anti-Leishmania and immunosuppressive chemotherapy is critical to reduce the mortality of VL associated HLH.     

High levels of oxysterol sulfates in serum of patients with steroid sulfatase deficiency

Steroid sulfatase (STS) deficiency is the underlying cause of the skin condition known as recessive X-linked ichthyosis (RXLI). RXLI patients show scales on their skin caused by high concentrations of cholesterol sulfate (CS), as they are not capable of releasing the sulfate group from its structure to obtain free cholesterol. CS has been reported, so far, as the sole sulfated steroid with increased concentrations in the blood of RXLI patients. A non-targeted LC-MS approach in negative mode detection (LC-MS precursor ion scan mode) was applied to serum samples of 12 RXLI patients and 19 healthy males. We found that CS was not the only sulfated compound consistently elevated in RXLI patients, because a group of compounds with a m/z of 481 was found in high concentrations too. Further LC-MS/MS demonstrated that the main contributor to the m/z 481 signal in RXLI serum is 27-hydroxycholesterol-3-sulfate (27OHC3S). Accordingly, a new method for 27OHC3S quantification in the context of RXLI has been developed and validated. Other hydroxycholesterol sulfate compounds were elevated as well in RXLI patients.     

SLAM-associated protein deficiency causes imbalanced early signal transduction and blocks downstream activation in T cells from X-linked lymphoproliferative disease patients

Deficiency of SAP (SLAM (signaling lymphocyte activation molecule)-associated protein) protein is associated with a severe immunodeficiency, the X-linked lymphoproliferative disease (XLP) characterized by an inappropriate immune reaction against Epstein-Barr virus infection often resulting in a fatal clinical course. Several studies demonstrated altered NK and T cell function in XLP patients; however, the mechanisms underlying XLP disease are still largely unknown. Here, we show that non-transformed T cell lines obtained from XLP patients were defective in several activation events such as IL-2 production, CD25 expression, and homotypic cell aggregation when cells were stimulated via T cell antigen receptor (TCR).CD3 but not when early TCR-dependent events were bypassed by stimulation with phorbol 12-myristate 13-acetate/ionomycin. Analysis of proximal T cell signaling revealed imbalanced TCR.CD3-induced signaling in SAP-deficient T cells. Although phospholipase C gamma 1 phosphorylation and calcium response were both enhanced in T cells from XLP patients, phosphorylation of VAV and downstream signal transduction events such as mitogen-activated protein kinase phosphorylation and IL-2 production were diminished. Importantly, reconstitution of SAP expression by retroviral-mediated gene transfer completely restored abnormal signaling events in T cell lines derived from XLP patients. In conclusion, SAP mutation or deletion in XLP patients causes profound defects in T cell activation, resulting in immune deficiency. Moreover, these data provide evidence that SAP functions as an essential integrator in early TCR signal transduction.     

Decreased Interleukin-10 Responses in Children with Severe Mycoplasma pneumoniae Pneumonia

Several cytokines may play roles in the immunological pathogenesis of mycoplasmal pneumonia caused by Mycoplasma pneumoniae. In this study, we investigated serum cytokine profiles in children with mycoplasmal pneumonia. The serum levels of interleukin (IL)-8, IL-10, and IL-18 were examined using ELISA kits in 34 patients with M. pneumoniae infection (Group 1, 11 with severe mycoplasmal pneumonia; Group 2, 13 with mild mycoplasmal pneumonia; Group 3, 10 with asthma) and 32 age-matched, non-infected controls. The serum levels of IL-8, IL-10, and IL-18 increased significantly in patients with mycoplasmal pneumonia compared with those in controls (P<0.01). The serum levels of IL-10 decreased significantly in Group 1 compared with those in Group 2 (P<0.01). The serum levels of IL-18 increased significantly in Group 1 compared with those in Group 2 (P<0.01). The serum levels of IL-10 and IL-18 decreased significantly in 10 M. pneumoniae-infected patients with asthma compared with those in 24 M. pneumoniae-infected patients without asthma (P<0.01). We examined the level of interleukins (IL-8, IL-10 and IL-18) after the patients started therapy. The data showed that IL-18 were lower after therapy (P<0.01). Collectively, our data suggested that these cytokines may be involved in the pathogenesis of mycoplasmal pneumonia.     

Prognostic significance of X-linked inhibitor of apoptosis protein in solid tumors: A systematic review and meta-analysis

X-linked inhibitor of apoptosis protein (XIAP) is aberrantly expressed in solid tumors. Considering conflicting data, we conducted this meta-analysis to investigate its prognostic role. Electronic databases were searched to collect studies about associations between XIAP expressions and survival outcomes. Hazard ratio (HR), odds ratio (OR), and 95% confidence interval (CI) were utilized as effect size estimates. A total of 3,794 patients from 21 published studies were included. The results revealed that high XIAP expressions correlated with age (OR = 2.02; 95% CI, 1.07–3.84), lymph node metastasis (OR = 1.69; 95% CI, 1.02–2.77), histological grade (OR = 2.04; 95% CI, 1.01–4.11), and tumor stage (OR = 2.18; 95% CI, 1.20–3.96). The combined HR revealed that high XIAP expressions associated with poor overall survival (OS) (HR = 1.60; 95% CI, 1.22–2.10). Our study suggested high XIAP expressions may be indicative of poor prognosis in solid tumors.     

Clinical associations of serum interleukin-17 in systemic lupus erythematosus

Introduction

Serum interleukin (IL)-17 concentrations have been reported to be increased in systemic lupus erythematosus (SLE), but associations with clinical characteristics are not well understood. We characterized clinical associations of serum IL-17 in SLE.

Methods

We quantified IL-17 in serum samples from 98 SLE patients studied cross-sectionally, and in 246 samples from 75 of these patients followed longitudinally over two years. Disease activity was recorded using the SLE Disease Activity Index (SLEDAI)-2k. Serum IL-6, migration inhibitory factor (MIF), and B cell activating factor of the tumour necrosis factor family (BAFF) were also measured in these samples.

Results

Serum IL-17 levels were significantly higher in SLE patients compared to healthy donors (P <0.0001). No correlation was observed between serum IL-17 and SLEDAI-2k, at baseline or during longitudinal follow-up. However, we observed that SLEDAI-2k was positively correlated with IL-17/IL-6 ratio. Serum IL-17 was significantly increased in SLE patients with central nervous system (CNS) disease (P = 0.0298). A strong correlation was observed between serum IL-17 and IL-6 (r = 0.62, P <0.0001), and this relationship was observed regardless of disease activity and persisted when integrating cytokine levels over the period observed (r = 0.66, P <0.0001). A strong correlation of serum IL-17 was also observed with serum BAFF (r = 0.64, P <0.0001), and MIF (r = 0.36, P = 0.0016).

Conclusions

Serum IL-17 concentration correlates poorly with SLE disease activity but is significantly elevated in patients with CNS disease. IL-17/IL-6 ratio may be more useful than IL-17 or IL-6 alone to characterize Th17-driven disease, such as SLE. The association of other cytokines with serum IL-17 suggests that IL-17 may drive activation of diverse immune pathways in SLE.     

Increased circulating levels and salivary gland expression of interleukin-18 in patients with Sjögren's syndrome: relationship with autoantibody production and lymphoid organization of the periductal inflammatory infiltrate

IL-18, an immunoregulatory and proinflammatory cytokine, has been shown to play an important pathogenic role in Th1-driven autoimmune disorders. In this study, we evaluated the circulating levels and salivary-gland expression of IL-18 in patients with Sjögren''s syndrome (SS), a mainly Th1-mediated disease. IL-18 serum levels were measured by ELISA in 37 patients with primary SS, 42 with rheumatoid arthritis, and 21 normal controls. We demonstrated high IL-18 serum levels in SS, similar to those in rheumatoid arthritis patients and significantly higher than in controls (P < 0.01). In addition, IL-18 serum concentrations were significantly higher in anti-SSA/Ro⁺ and anti-SSB/La⁺ than in anti-SSA/Ro^- and anti-SSB/La^- SS patients (respectively, P = 0.01, P < 0.01). Serum IL-18 correlated strongly with anti-SSA/Ro (P = 0.004) and anti-SSB/La (P = 0.01) titers. Salivary gland IL-18 expression was investigated by single/double immunohistochemistry in 13 patients with primary SS and in 10 with chronic sialoadenitis, used as controls. The expression of IL-18 was also examined in periductal inflammatory foci in relation to the acquisition of features of secondary lymphoid organs such as T–B compartmentalization, formation of follicular dendritic cell networks, and presence of germinal-center-like structures. IL-18 expression in SS salivary glands was detected in 28 of 32 periductal foci of mononuclear cells (87.5%), while no IL-18 production by infiltrating cells was detected in patients with chronic sialoadenitis. Within the inflammatory foci, IL-18 immunoreactivity co-localized almost exclusively with CD68⁺ macrophages. In addition, IL-18 was found in 15 of 19 foci (78.9%) with no evidence of T–B cell compartmentalization (nonsegregated) but in 100% of the segregated aggregates, both in T- and B-cell-rich areas. Strikingly, IL-18 was strongly expressed by CD68⁺ tingible body macrophages in germinal-centre-like structures both in SS salivary glands and in normal lymph nodes. IL-18 expression was observed in the ducts of all SS biopsies but in only 4 of 10 patients with nonspecific chronic sialoadenitis (P < 0.01). This study provides the first evidence of increased circulating levels and salivary gland expression of IL-18 in SS, suggesting an important contribution of this cytokine to the modulation of immune inflammatory pathways in this condition.     

The Expression of Tristetraprolin and Its Relationship with Urinary Proteins in Patients with Diabetic Nephropathy

Objective

Tristetraprolin (TTP), also known as zinc finger protein 36, is an RNA binding protein that has a significant role in regulating the expression of mRNAs containing AU-rich elements. We postulated that TTP might regulate interleukin (IL)-6 and IL-18 expression in diabetes. This study aimed to test the hypothesis that the levels of TTP are correlated with nephropathy in patients with type 2 diabetes.

Methods

Eighty-seven patients (61.3±9.6 years old) who had been diagnosed with type 2 diabetes mellitus and 41 age and sex matched healthy control subjects were enrolled. The diabetes patients were classified into those without proteinuria, with microalbuminuria, and with clinical proteinuria groups according to the ratio of urinary excretion of albumin/creatinine (ACR).

Results

Serum and urinary levels of IL-6 and IL-18 were significantly elevated, but those of TTP were significantly decreased in patients with diabetes as compared with control subjects. In addition, serum and urinary levels of IL-6 and IL-18 were significantly higher, but those of TTP were significantly lower in patients with proteinuria than in patients without proteinuria or with microalbuminuria. There was a significant correlation between serum TTP and IL-6/IL-18 (correlation coefficients of -0.572 and -0.685, P < 0.05).

Conclusion

These results show that diabetes with clinical proteinuria is accompanied by decreased urinary and serum level of TTP and increased levels of IL-6 and IL-18. Decreased TTP expression might occur prior to the increase in IL-6 and IL-18, and decrease of TTP might provide an earlier marker for glomerular dysfunction than IL-6 and IL-18.     

Transgenic Mice Overexpressing Serum Retinol-Binding Protein Develop Progressive Retinal Degeneration through a Retinoid-Independent Mechanism

Serum retinol-binding protein 4 (RBP4) is the sole specific transport protein for retinol in the blood, but it is also an adipokine with retinol-independent, proinflammatory activity associated with obesity, insulin resistance, type 2 diabetes, and cardiovascular disease. Moreover, two separate studies reported that patients with proliferative diabetic retinopathy have increased serum RBP4 levels compared to patients with mild or no retinopathy, yet the effect of increased levels of RBP4 on the retina has not been studied. Here we show that transgenic mice overexpressing RBP4 (RBP4-Tg mice) develop progressive retinal degeneration, characterized by photoreceptor ribbon synapse deficiency and subsequent bipolar cell loss. Ocular retinoid and bisretinoid levels are normal in RBP4-Tg mice, demonstrating that a retinoid-independent mechanism underlies retinal degeneration. Increased expression of pro-interleukin-18 (pro-IL-18) mRNA and activated IL-18 protein and early-onset microglia activation in the retina suggest that retinal degeneration is driven by a proinflammatory mechanism. Neither chronic systemic metabolic disease nor other retinal insults are required for RBP4 elevation to promote retinal neurodegeneration, since RBP4-Tg mice do not have coincident retinal vascular pathology, obesity, dyslipidemia, or hyperglycemia. These findings suggest that elevation of serum RBP4 levels could be a risk factor for retinal damage and vision loss in nondiabetic as well as diabetic patients.     

Phosphorylation of Smac by JNK3 attenuates its interaction with XIAP

Here we demonstrate that JNK3 can phosphorylate Smac. Smac phosphorylation attenuates its ability to activate apoptosome activity in HeLa S-100 cell lysates. Addition of the X-linked inhibitor of apoptosis protein (XIAP) to the S-100 markedly suppresses apoptosome activity, and this suppressive effect of XIAP is neutralized by adding unphosphorylated Smac, but not phosphorylated Smac. Furtherover, JNK3-mediated phosphorylation of Smac markedly attenuates the interaction between Smac and XIAP, as measured by BIACORE assays and non-denaturing gel shift assays. When JNK3 activity is down-regulated in etoposide-induced HeLa cells by transiently overexpressing a dominant negative version of JNK3 (DN-JNK3), the caspase-3 activity as well as PARP cleavages are markedly enhanced. And the interaction of Smac with XIAP also increases by down-regulating JNK3 activity under the same conditions. These results suggest that JNK3 activity can attenuate the progression of apoptosis through a novel mechanism of action, the down-regulation of interaction between Smac and XIAP.     

IL-18 and related function proteins associated with tuberculosis severity and screening for active TB among patients with non-mycobacterial community-acquired pneumonia (CAP)

BackgroundDifferentiation of active pulmonary tuberculosis (TB) from non-mycobacterial community-acquired pneumonia (CAP) still remains a diagnostic challenge.ObjectiveThe study aimed to quantify the IL-18, IFN-γ, IL-18BP, IL-37, and IP-10 levels in serum and Mycobacterium tuberculosis (M.tb) antigens-stimulated blood cultures from TB or CAP patients and explore if the proteins can be a useful basis for discriminating these diseases.MethodsIn total, 124 Polish adults, including mild/moderate (M/MTB) or advanced (ATB) TB patients, and CAP patients, were enrolled in the study. The concentrations of IL-18, IL-18BP, IFN-γ, IL-37, and IP-10 in sera and M.tb-stimulated cultures were measured by ELISA.ResultsThe most specific and sensitive serum proteins discriminating TB from CAP were IP-10 and IL-18BP; however, IP-10 had the highest AUC in the ROC curve for the diagnosis. Serum IP-10 and IL-18BP levels increased significantly in M/MTB or ATB groups. The IL-18BP elevation in ATB group was accompanied by an increase in IL-18. No single protein measured in M.tb-stimulated cultures differed TB from CAP patients.ConclusionsThe combined analysis of serum IL-18BP and IP-10 might be considered as an auxiliary tool in the differentiation of TB from CAP.     

X连锁凋亡抑制蛋白的功能及其在肿瘤中的作用

X连锁凋亡抑制蛋白(X-linked inhibitor of apoptosis,XIAP)是目前发现的最具特征性与作用最强的内源性凋亡抑制蛋白质.XIAP特征性结构是其BIR结构域和RING结构域,它们都是XIAP发挥抗凋亡作用的重要结构.多种内源性抑制蛋白质(XAF1、Smac和Omi)能通过不同的方式抑制XIA...