Structural mechanism of DNA recognition by the p202 HINa domain: insights into the inhibition of Aim2-mediated inflammatory signalling

Li, H.; Wang, J.; Cao, Lusha; Wang, Z.-X.; Wu, Jiawei

doi:10.1107/s2053230x1303135x

Cited by 19 publications

(20 citation statements)

References 40 publications

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“…In the absence of DNA ALRs are in an autoinhibited state with PYD and HIN domains. This suggests a mechanism of AIM2 activation in which binding of DNA to the HIN domain releases the PYD from its interaction with the HIN domain, thereby promoting PYD‐PYD interaction with ASC and inflammasome assembly …”

Section: Aim2 Detection Of Dnamentioning

confidence: 99%

The AIM2 inflammasome: Sensor of pathogens and cellular perturbations

Lugrin

Martinon

2017

Immunological Reviews

290

205

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Recognition of pathogens and altered self must be efficient and highly specific to orchestrate appropriate responses while limiting excessive inflammation and autoimmune reaction to normal self. AIM2 is a member of innate immune sensors that detects the presence of DNA, arguably the most conserved molecules in living organisms. However, AIM2 achieves specificity by detecting altered or mislocalized DNA molecules. It can detect damaged DNA, and the aberrant presence of DNA within the cytosolic compartment such as genomic DNA released into the cytosol upon loss of nuclear envelope integrity. AIM2 is also a key sensor of pathogens that detects the presence of foreign DNA accumulating in the cytosol during the life cycle of intracellular pathogens including viruses, bacteria, and parasites. AIM2 activation initiates the assembly of the inflammasome, an innate immune complex that leads to the activation of inflammatory caspases. This triggers the maturation and secretion of the cytokines IL-1β and IL-18. It can also initiate pyroptosis, a proinflammatory form of cell death. The AIM2 inflammasome contributes to physiological responses and diseases. It is a key player in host defenses, but its deregulation can contribute immune-linked diseases, such as autoinflammatory and autoimmune pathologies. Moreover, AIM2 may play a role in cancer development. Recent studies have shown that the detection of self-DNA species by AIM2 is an important factor that contributes to diseases associated with perturbation of cellular homeostasis. Thus, in addition of being a sensor of pathogen associated molecular patterns (PAMPs), the AIM2 inflammasome is emerging as a key guardian of cellular integrity.

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Section: Aim2 Detection Of Dnamentioning

confidence: 99%

The AIM2 inflammasome: Sensor of pathogens and cellular perturbations

Lugrin

Martinon

2017

Immunological Reviews

290

205

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“…Furthermore, studies involving overexpression of AIM2 in transfected cells, followed by immunoprecipitation-Western assays, indicated that the AIM2 protein binds with IFI16 protein [38] and can homodimerize [39]. Interestingly, studies indicated that the HIN domain in certain PYHIN-family proteins also allows proteins to form homo and heterodimers [41][42][43][44][45][46]. For example, the HIN2 domain in the p202 protein formed homodimers and bound to the HIN domain of Aim2 protein [42].…”

Section: Homo and Heterodimerization By Aim2/aim2mentioning

confidence: 99%

Absent in melanoma 2 proteins in the development of cancer

Choubey

2016

Cell. Mol. Life Sci.

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Recent studies utilizing chemical-induced colitis-associated and sporadic colon cancer in mouse models indicated a protective role for absent in melanoma 2 (Aim2) in colon epithelial cells. Accordingly, mutations in the human AIM2 gene have been found in colorectal cancer (CRC), and reduced expression of AIM2 in CRC is associated with its progression. Furthermore, the overexpression of AIM2 protein in human cancer cell lines inhibits cell proliferation. Interferon-inducible Aim2 and AIM2 are members of the PYHIN (PYRIN and HIN domain-containing) protein family and share ~57 % amino acid identity. The family also includes murine p202, human PYRIN-only protein 3, and IFI16, which negatively regulate Aim2/AIM2 functions. Because the CRC incidence and mortality rates are higher among men compared with women and the expression of Aim2/AIM2 proteins and their regulators is dependent upon age, gender, and sex hormones, we discuss the potential roles of Aim2/AIM2 in the development of cancer. An improved understanding of the biological functions of the AIM2 in the development of CRC will likely identify new therapeutic approaches to treat patients.

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“…Expression of p202 is induced by interferon, and as negative feedback regulation p202 inhibits the inflammatory function of AIM2 [14]. Crystal structures of the p202 HIN1/dsDNA complexes show that the two OB folds are very similar to those of AIM2, but that the dsDNA binds p202 HIN1 at an almost opposite surface compared with that used in AIM2 HIN (Figure 3d, 3e) [30, 32, 33]. Surprisingly, the HIN2 domain of p202 does not interact with dsDNA [33].…”

Section: Dna Recognition and Regulation By Alr Hin Domainsmentioning

confidence: 99%

“…First, p202 binds dsDNA at a higher affinity than AIM2, and therefore competes with AIM2 for access to dsDNA. Second, the direct interaction between p202 HIN2 and AIM2 HIN domains may allow incorporation of p202 onto the same dsDNA that AIM2 interacts with, thereby diluting the effective concentration of AIM2 on the dsDNA [30, 32, 33] (Figure 3f). Thus, AIM2 PYD oligomerization and downstream signaling may be inhibited.…”

Section: Dna Recognition and Regulation By Alr Hin Domainsmentioning

confidence: 99%

The hierarchical structural architecture of inflammasomes, supramolecular inflammatory machines

Hauenstein

Zhang

2015

Current Opinion in Structural Biology

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Inflammasomes are caspase-1 activating, molecular inflammatory machines that proteolytically mature pro-inflammatory cytokines and induce pyroptotic cell death during innate immune responses. Recent structural studies of proteins that constitute inflammasomes have yielded fresh insights into their assembly mechanisms. In particular, these include a crystal structure of the CARD-containing NOD-like receptor NLRC4, the crystallographic and electron microscopy (EM) studies of the dsDNA sensors AIM2 and IFI16, and of the regulatory protein p202, and the cryo-EM filament structure of the PYD domain of the inflammasome adapter ASC. These data suggest inflammasome assembly that starts with ligand recognition and release of autoinhibition followed by step-wise rounds of nucleated polymerization from the sensors to the adapters, then to caspase-1. In this elegant manner, inflammasomes form by an “all-or-none” cooperative mechanism, thereby amplifying the activation of caspase-1. The dense network of filamentous structures predicted by this model has been observed in cells as micron-sized puncta.

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Structural mechanism of DNA recognition by the p202 HINa domain: insights into the inhibition of Aim2-mediated inflammatory signalling

Cited by 19 publications

References 40 publications

The AIM2 inflammasome: Sensor of pathogens and cellular perturbations

The AIM2 inflammasome: Sensor of pathogens and cellular perturbations

Absent in melanoma 2 proteins in the development of cancer

The hierarchical structural architecture of inflammasomes, supramolecular inflammatory machines

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