Cytoplasmic localization of the interferon‐inducible protein that is encoded by the <i>AIM2</i> (absent in melanoma) gene from the 200‐gene family

Choubey, Divaker; Walter, Scott; Geng, Yanbiao; Hong, Xin

doi:10.1016/s0014-5793(00)01571-4

Cited by 56 publications

(53 citation statements)

References 19 publications

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“…In contrast, p204 was present and inducible by Ad5CiG. Both AIM2 and p204 are classified as IFNinducible transcripts (3,4), so the difference in response to rAd5CiG infection indicates that possible novel regulatory mechanisms are operating with these hin200 genes. At the level of DNA sensor expression, there was no overt deficiency in the cell lines examined.…”

Section: Discussionmentioning

confidence: 98%

Cell-Specific Regulation of Nucleic Acid Sensor Cascades: a Controlling Interest in the Antiviral Response

Stein

Lam

Falck-Pedersen

2012

J Virol

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In this study, we examined the capacities of non-antigen-presenting cell types to propagate antiviral signals following infection with recombinant adenovirus or by direct nucleic acid transfection. Three murine cell lines (RAW264.7 macrophages as a positive control, FL83B hepatocytes, and MS1 endothelial cells) were assessed following exposure to adenovirus, DNA, or RNA ligands. Based on primary (interferon response factor 3 [IRF3] phosphorylation) and secondary (STAT1/2 phosphorylation) response markers, we found each cell line presented a unique response profile: RAW cells were highly responsive, MS1 cells were modified in their response, and FL83B cells were essentially nonresponsive. Comparative reverse transcription-quantitative PCR (RT-qPCR) of nucleic acid sensing components revealed major differences between the three cell types. A prominent difference was at the level of adaptor molecules; TRIF, MyD88, MAVS, and STING. TRIF was absent in MS1 and FL83B cells, whereas MyD88 levels were diminished in FL83B hepatocytes. These differences resulted in compromised TLR-mediated activation. While the cytosolic adaptor MAVS was well represented in all cell lines, the DNA adaptor STING was deficient in FL83B hepatocytes (down by nearly 3 log units). The absence of STING provides an explanation for the lack of DNA responsiveness in these cells. This hypothesis was confirmed by acquisition of IRF3 activation in Flag-STING FL83B cells following DNA transfection. To consolidate the central role of adaptors in MS1 endothelial cells, short hairpin RNA (shRNA) knockdown of STING and MAVS resulted in a ligand-specific loss of IRF3 responsiveness. In contrast to the requirement for specific adaptor proteins, a requirement for a specific DNA sensor (AIM2, DDx41, or p204) in the IRF3 activation response was not detected by shRNA knockdown in MS1 cells. The data reveal that cell-specific regulation of nucleic acid sensing cascade components influences antiviral recognition responses, that controlling levels of adaptor molecules is a recurring strategy in regulating antiviral recognition response functions, and that comparative RT-qPCR has predictive value for antiviral/innate response functions in these cells.

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Section: Discussionmentioning

confidence: 98%

Cell-Specific Regulation of Nucleic Acid Sensor Cascades: a Controlling Interest in the Antiviral Response

Stein

Lam

Falck-Pedersen

2012

J Virol

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“…The amino acid sequence of Aim2 or AIM2 protein lacks a classical nuclear localization signal (NLS) [2,37]. Therefore, it is intriguing that both Aim2 and AIM2 are detected in the nucleus to a varying extent in certain normal and cancer cell types examined (Table 2).…”

Section: Cell-type-dependent Sub-cellular Localization Of Aim2/aim2mentioning

confidence: 99%

“…Notably, IFN-c treatment of THP-1 or PMA-treated THP-1 cells robustly increased AIM2 protein levels in the cytoplasm and HNPCC-associated small bowl cancer (SBC) Loss of expression (frame-shift mutation) Poor prognosis [27] Colorectal cancer Loss of expression (microsatellite instability) Poor prognosis [29,30] Nasopharyngeal carcinoma (NPC) Overexpression Correlated with survival [31] Oral squamous cell carcinoma (OSCC) Overexpression p53-dependent inhibition [32] Non-small cell lung cancer (NSCLC) Overexpression Poor prognosis [33] Oral cancer Overexpression Not known [34] Cervical cancer Overexpression (amplification of 1q22-23 region) Not known [75] D. Choubey very little protein was detected in the nucleus. Furthermore, constitutively overexpressed human AIM2 protein in the murine AKR-2B fibroblasts (spontaneously immortalized) was primarily detected in the cytoplasm [37]. However, when constitutively overexpressed in human melanoma cell line UACC903, the AIM2 protein was detected within the nucleus of transfected or interferon-treated cells [39].…”

Section: Cell-type-dependent Sub-cellular Localization Of Aim2/aim2mentioning

confidence: 99%

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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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“…IFI16 dimerizes via PYD association, and has the ability to bind to DNA and function as a transcriptional repressor [135]. Absent in melanoma 2 (AIM2) contains a single HIN-200 repeat, localizes primarily to the cytoplasm, and is involved in suppression of tumorigenicity in melanoma, by inhibiting cell proliferation and induction of apoptosis [136,137]. This observation correlates with its down-regulation in cancers [138,139].…”

Section: Signaling By Hin-200 Proteinsmentioning

confidence: 97%

The PYRIN Domain in Signal Transduction

Stehlik¹

2007

CPPS

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The Death Domain Fold superfamily of evolutionarily conserved protein-protein interaction domains consists of 4 subfamilies: the death domain, the death effector domain, the caspase recruitment domain, and the PYRIN domain. Interaction of Death Domain Fold containing proteins modulates the activity of several downstream effectors, such as caspases and transcription factors. Recent studies provide evidence for not only homotypic-, but also heterotypic interactions among different sub-families, and even unconventional non-death domain fold interactions. As the number of potential protein associations among Death Domain Fold containing proteins expands and their influence on cellular responses increases, a challenging field for new investigations opens up. This review will focus on PYRIN domain-containing proteins and discuss the recent advances that provide strong evidence that PYRIN domain-mediated signal transduction has broad implications on cellular functions, including innate immunity, inflammation, differentiation, apoptosis, and cancer. Keywords apoptosis; cancer; CARD domain; caspase activation; death domain fold; inflammation; interleukin-1; leucine rich region; NACHT domain; NF-κB; pathogen associated molecular pattern; pathogen recognition receptor; PYRIN domain; signal transduction THE DEATH DOMAIN FOLD SUPERFAMILY OF PROTEIN INTERACTION DOMAINSThe death domain fold (DDF) is a highly conserved protein interaction domain spanning approximately 90 amino acid residues. This superfamily consists of four subfamilies: The death domain (DD), the death effector domain (DED), the caspase recruitment domain (CARD), and the pyrin N-terminal homology domain (PYRIN domain, PYD). Subfamilies are mainly defined by sequence homology, and display a common three-dimensional structure. However, the sequence identity between the subfamilies is usually lower than 25%, and even within one family mainly restricted to conserved residues of the hydrophobic core.DDF containing proteins have been linked to the activation of caspases and subsequent initiation of apoptosis by the induced proximity mechanism. However, several additional downstream effectors link these domains not only to apoptosis, but also immunity, NIH Public Access DD-DD, DED-DED, CARD-CARD, PYD-PYD).Yet, recent evidence demonstrated their capability to also form heterotypic interactions among family members, and even unconventional, non-DDF interactions, thereby increasing the number of potential protein associations and cellular responses. The first evidence for unconventional, non-DDF interactions came from the observation that the DED of PEA-15 (PED) interacts with the C-terminal domain of ERK [1]. Also, the DD of Fas (Apo-1, CD95, TNFRSF6) was suggested to associate with calmodulin in a Fas ligand and Ca 2+ -dependent manner [2]. The apoptosis repressor with a CARD (ARC CARD2, Myp) can disrupt the intrinsic, mitochondrial apoptosis pathway by association of its CARD with the C-terminal domain of Bax. By heterotypic interaction, ARC disrupts the ext...

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Cytoplasmic localization of the interferon‐inducible protein that is encoded by the AIM2 (absent in melanoma) gene from the 200‐gene family

Cited by 56 publications

References 19 publications

Cell-Specific Regulation of Nucleic Acid Sensor Cascades: a Controlling Interest in the Antiviral Response

Cell-Specific Regulation of Nucleic Acid Sensor Cascades: a Controlling Interest in the Antiviral Response

Absent in melanoma 2 proteins in the development of cancer

The PYRIN Domain in Signal Transduction

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