AIM2

Last updated
AIM2
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases AIM2 , PYHIN4, absent in melanoma 2
External IDs OMIM: 604578 MGI: 2686159 HomoloGene: 83226 GeneCards: AIM2
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_004833
NM_001348247

NM_001013779

RefSeq (protein)

NP_004824
NP_001335176

NP_001013801

Location (UCSC) Chr 1: 159.06 – 159.19 Mb Chr 1: 173.35 – 173.47 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Interferon-inducible protein AIM2 also known as absent in melanoma 2 or simply AIM2 is a protein that in humans is encoded by the AIM2 gene. [5] [6]

Contents

AIM2 is a cytoplasmic sensor found in hematopoietic cells that recognizes the presence of double-stranded DNA (dsDNA) of microbial or host cellular origin. [7] AIM2-like receptor (ALR) family was founded on AIM2 and now consists of four members in human genome. [8] Activated AIM2 recruits apoptosis-associated speck-like protein containing a CARD (ASC), resulting in caspase-1 binding, and forming of AIM2 inflammasome. This signaling contributes to the defense against bacterial and viral DNA.

Structure

Proteins belonging to ALR family usually contain an N-terminal pyrin (PYD) domain, and one or two HIN domains. AIM2 consists of two domains connected through a long linker: an N-terminal PYD domain (amino acids 1-87), and a C-terminal HIN-200 domain (amino acids 138–337). The PYD domain mediates homotypic protein-protein interaction, while the HIN domain binds to DNA with its two tandem oligonucleotide/oligosaccharide binding (OB) folds. [9]

Function

AIM2 is a component of the innate immune system that functions as a cytoplasmic dsDNA sensor playing a role in antiviral and antibacterial defenses, as well as in autoimmune diseases involving self DNA. Together with the adaptor ASC protein AIM2 forms a caspase-1 activating complex known as the AIM2 inflammasome.

The first step in the formation of AIM2 inflammasome is DNA binding. The HIN domain of AIM2 binds to both strands of B-form dsDNA (either viral, bacterial, or even host) in a sequence-independent manner. However, the DNA sequence must be at least 80 base pairs in length. [10] The interaction is mainly electrostatic, where positively charged amino acid residues are coordinating with phosphates and sugar moieties on DNA backbone. Binding of dsDNA displaces PYD domain, which then engages the downstream inflammasome adaptor protein ASC through homotypic PYD-PYD interactions. [11] ASC is a bipartite PYD-CARD-containing protein. CARD domain of ASC recruits procaspase-1 (CARD-CARD interaction) to the complex creating the basic structural elements of the AIM2 inflammasome. Caspase-1 autoactivates and processes cleavage of pro-IL-1β, pro-IL-18, and gasdermin D. The N-terminal fragment of gasdermin D induces pyroptosis that allows mature cytokines IL-1β, and IL-18 to be released from the cell.  

Regulation

Regulation of inflammasome assembly is essential for cellular homeostasis maintenance. AIM2 activation is inhibited by the mouse protein p202 that consists of two HIN domains and lacks the PYD. ASC protein is not recruited due to the absence of PYD domain. The HIN1 domain binds to DNA, whereas HIN2 domain interacts with AIM2. HIN2 domain does not block the DNA binding surface of AIM2, hence, DNA binding affinity of AIM2 remains unaffected. It is believed that binding of p202 to DNA and AIM2 might attain a balance between host defense and pathological DNA-induced inflammation. When both p202 and AIM2 are present in equal amounts, there is a competition for dsDNA binding. [12]

A novel transcript isoform of human IFI16-designated IFI16-β has been also shown to inhibit the AIM2 inflammasome assembly. Its domain structure is similar to that of mouse p202 as it contains two HIN domains. Analogously it interacts with AIM2, competes in dsDNA binding, and disrupts ASC recruitment. [13] According to studies of p202 and IFI16-β, it appears that proteins expressing two HIN domains bind to dsDNA more robustly than proteins containing a single HIN domain. [14]

Regarding post-translational modifications, there is limited knowledge. However, it has been reported that TRIM11 binds AIM2 and leads to its degradation. Hence, it might be a negative regulator of the AIM2 inflammasome. [15]

Clinical relevance

A broad range of microbes is sensed by AIM2, leading to protective inflammasome-mediated host responses. Recent publications have shown that AIM2 inflammasome also plays roles in non-infectious diseases.

Infection

Bacteria

Bacterial DNA is released into cytoplasm during infection of a host cell, where it is recognized by AIM2 and other cytoplasmic DNA sensors. AIM2 has been shown to recognize a number of pathogenic bacteria – Francisella tularensis , Listeria monocytogenes , Streptococcus pneumoniae , Mycobacterium species, Porphyromonas gingivalis , Staphylococcus aureus , Brucella abortus , and Chlamydia muridarum . [7] Type I IFNs augment the activity of the AIM2 inflammasome during bacterial infection. [16] [17]

Viruses

AIM2 inflammasome plays a crucial role in the defense against viral infection as genetic material from DNA viruses that enter the cytoplasm can be recognized. However, AIM2 does not respond to all DNA viruses. To date, only mouse cytomegalovirus (MCMV), vaccinia virus, and human papillomaviruses have been observed to induce AIM2 inflammasome. [7]

Other pathogens

Moreover, AIM2 has been shown to mediate host defense to the fungal pathogen Aspergillus fumigatus [18] and the protozoan Plasmodium berghei . [19]

Cancer

The gene encoding AIM2 was originally isolated from human melanoma cells. [5] AIM2 has been shown to suppress the development of tumors. However, the expression of AIM2 was observed to be differential in a range of tumor tissues suggesting that it may have unique roles in different cancer types. Recent studies investigating AIM2 function in cancer highlight the potential role of therapies inhibiting the AKT pathway in the treatment of cancer associated with AIM2 mutations. [7]

Inflammatory, autoimmune, and other pathological conditions

The accumulation of DNA in the cytosol can serve as an endogenous danger signal triggering AIM2 inflammasome. Aberrant activation of AIM2 from self-DNA is a key driver of inflammatory and autoimmune diseases. Elevated levels of AIM2 expression are found in skin cells from people with acute and chronic skin conditions, including psoriasis, atopic dermatitis, and contact dermatitis. Increased expression of AIM2 has also been reported in patients with inflammatory bowel disease and liver inflammation. Moreover, AIM2 might be involved in inflammation and cell death of the brain. [7] In systemic lupus erythematosus, lysosome dysfunction allows DNA to gain access to the cytosol and activate AIM2 resulting in increased type 1 interferon production. [20]

Related Research Articles

<span class="mw-page-title-main">Interferon</span> Signaling proteins released by host cells in response to the presence of pathogens

Interferons are a group of signaling proteins made and released by host cells in response to the presence of several viruses. In a typical scenario, a virus-infected cell will release interferons causing nearby cells to heighten their anti-viral defenses.

<span class="mw-page-title-main">Endogenous retrovirus</span> Inherited retrovirus encoded in an organisms genome

Endogenous retroviruses (ERVs) are endogenous viral elements in the genome that closely resemble and can be derived from retroviruses. They are abundant in the genomes of jawed vertebrates, and they comprise up to 5–8% of the human genome.

<span class="mw-page-title-main">Caspase 1</span> Protein-coding gene in the species Homo sapiens

Caspase-1/Interleukin-1 converting enzyme (ICE) is an evolutionarily conserved enzyme that proteolytically cleaves other proteins, such as the precursors of the inflammatory cytokines interleukin 1β and interleukin 18 as well as the pyroptosis inducer Gasdermin D, into active mature peptides. It plays a central role in cell immunity as an inflammatory response initiator. Once activated through formation of an inflammasome complex, it initiates a proinflammatory response through the cleavage and thus activation of the two inflammatory cytokines, interleukin 1β (IL-1β) and interleukin 18 (IL-18) as well as pyroptosis, a programmed lytic cell death pathway, through cleavage of Gasdermin D. The two inflammatory cytokines activated by Caspase-1 are excreted from the cell to further induce the inflammatory response in neighboring cells.

<span class="mw-page-title-main">NLRP3</span> Human protein and coding gene

NLR family pyrin domain containing 3 (NLRP3), is a protein that in humans is encoded by the NLRP3 gene located on the long arm of chromosome 1.

Pyroptosis is a highly inflammatory form of lytic programmed cell death that occurs most frequently upon infection with intracellular pathogens and is likely to form part of the antimicrobial response. This process promotes the rapid clearance of various bacterial, viral, fungal and protozoan infections by removing intracellular replication niches and enhancing the host's defensive responses. Pyroptosis can take place in immune cells and is also reported to occur in keratinocytes and some epithelial cells.

<span class="mw-page-title-main">TP53BP1</span> Protein-coding gene in the species Homo sapiens

Tumor suppressor p53-binding protein 1 also known as p53-binding protein 1 or 53BP1 is a protein that in humans is encoded by the TP53BP1 gene.

<span class="mw-page-title-main">ADAR</span> Mammalian protein found in Homo sapiens

The double-stranded RNA-specific adenosine deaminase enzyme family are encoded by the ADAR family genes. ADAR stands for adenosine deaminase acting on RNA. This article focuses on the ADAR proteins; This article details the evolutionary history, structure, function, mechanisms and importance of all proteins within this family.

<span class="mw-page-title-main">IFI16</span> Protein-coding gene in the species Homo sapiens

Gamma-interferon-inducible protein Ifi-16 (Ifi-16) also known as interferon-inducible myeloid differentiation transcriptional activator is a protein that in humans is encoded by the IFI16 gene.

<span class="mw-page-title-main">GBP2</span> Protein-coding gene in the species Homo sapiens

Interferon-induced guanylate-binding protein 2 is a protein that in humans is encoded by the GBP2 gene. GBP2 is a gene related to the superfamily of large GTPases which can be induced mainly by interferon gamma.

<span class="mw-page-title-main">NLRP12</span> Protein-coding gene in the species Homo sapiens

NACHT, LRR and PYD domains-containing protein 12 is a protein that in humans is encoded by the NLRP12 gene.

<span class="mw-page-title-main">ZBP1</span> Protein-coding gene in the species Homo sapiens

Z-DNA-binding protein 1, also known as DNA-dependent activator of IFN-regulatory factors (DAI) and DLM-1, is a protein that in humans is encoded by the ZBP1 gene.

<span class="mw-page-title-main">NOD-like receptor</span> Class of proteins

The nucleotide-binding oligomerization domain-like receptors, or NOD-like receptors (NLRs), are intracellular sensors of pathogen-associated molecular patterns (PAMPs) that enter the cell via phagocytosis or pores, and damage-associated molecular patterns (DAMPs) that are associated with cell stress. They are types of pattern recognition receptors (PRRs), and play key roles in the regulation of innate immune response. NLRs can cooperate with toll-like receptors (TLRs) and regulate inflammatory and apoptotic response.

<span class="mw-page-title-main">Inflammasome</span> Cytosolic multiprotein complex that mediates the activation of Caspase 1

Inflammasomes are cytosolic multiprotein oligomers of the innate immune system responsible for the activation of inflammatory responses. Activation and assembly of the inflammasome promotes proteolytic cleavage, maturation and secretion of pro-inflammatory cytokines interleukin 1β (IL-1β) and interleukin 18 (IL-18), as well as cleavage of gasdermin D. The N-terminal fragment resulting from this cleavage induces a pro-inflammatory form of programmed cell death distinct from apoptosis, referred to as pyroptosis, and is responsible for secretion of the mature cytokines, presumably through the formation of pores in the plasma membrane. Additionally, inflammasomes can be incorporated into larger cell death-inducing complexes called PANoptosomes, which drive another distinct form of pro-inflammatory cell death called PANoptosis.

Mitophagy is the selective degradation of mitochondria by autophagy. It often occurs to defective mitochondria following damage or stress. The process of mitophagy was first described over a hundred years ago by Margaret Reed Lewis and Warren Harmon Lewis. Ashford and Porter used electron microscopy to observe mitochondrial fragments in liver lysosomes by 1962, and a 1977 report suggested that "mitochondria develop functional alterations which would activate autophagy." The term "mitophagy" was in use by 1998.

<span class="mw-page-title-main">Pyrin domain</span>

A pyrin domain is a protein domain and a subclass of protein motif known as the death fold, the 4th and most recently discovered member of the death domain superfamily (DDF). It was originally discovered in the pyrin protein, or marenostrin, encoded by MEFV. The mutation of the MEFV gene is the cause of the disease known as Familial Mediterranean Fever. The domain is encoded in 23 human proteins and at least 31 mouse genes.

<span class="mw-page-title-main">NLRP11</span> Protein-coding gene in the species Homo sapiens

NOD-like receptor family pyrin domain containing 11 is a protein that in humans is encoded by the NLRP11 gene located on the long arm of human chromosome 19q13.42. NLRP11 belongs to the NALP subfamily, part of a large subfamily of CATERPILLER. It is also known as NALP11, PYPAF6, NOD17, PAN10, and CLR19.6

<span class="mw-page-title-main">Guanylate-binding protein</span>

In molecular biology, the guanylate-binding proteins family is a family of GTPases that is induced by interferon (IFN)-gamma. GTPases induced by IFN-gamma are key to the protective immunity against microbial and viral pathogens. These GTPases are classified into three groups: the small 47-KD immunity-related GTPases (IRGs), the Mx proteins, and the large 65- to 67-kd GTPases. Guanylate-binding proteins (GBP) fall into the last class.

Immunogenic cell death is any type of cell death eliciting an immune response. Both accidental cell death and regulated cell death can result in immune response. Immunogenic cell death contrasts to forms of cell death that do not elicit any response or even mediate immune tolerance.

The cGAS–STING pathway is a component of the innate immune system that functions to detect the presence of cytosolic DNA and, in response, trigger expression of inflammatory genes that can lead to senescence or to the activation of defense mechanisms. DNA is normally found in the nucleus of the cell. Localization of DNA to the cytosol is associated with tumorigenesis, viral infection, and invasion by some intracellular bacteria. The cGAS – STING pathway acts to detect cytosolic DNA and induce an immune response.

<span class="mw-page-title-main">Dapansutrile</span> Chemical compound

Dapansutrile (OLT1177) is an inhibitor of the NLRP3 inflammasome.

References

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Further reading