Immunoproteasome

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An immunoproteasome is a type of proteasome that degrades ubiquitin-labeled proteins found in the cytoplasm in cells exposed to oxidative stress and proinflammatory stimuli. In general, proteasomes consist of a regulatory and a catalytic part. Immunoproteasomes are induced by interferon gamma (but also by other proinflammatory cytokines) and oxidative stress, which in the cell triggers the transcription of three catalytic subunits that do not occur in the classical proteasome. [1] Another possible variation of proteasome is the thymoproteasome, which is located in the thymus and folds to present peptides to naive T cells.

Contents

Structure

Structurally, immunoproteasome is a cylindrical protein complex composed of a catalytic 20S subunit and a 19S regulatory subunit. The catalytic subunit consists of four outer alpha rings and four inner beta rings. [2] In the classical proteasome, the beta (β) 1, β2 and β5 subunits have catalytic activity, which, however, in the immunoproteasome are replaced by the subunits LMP2 (alias β1i), MECL-1 (alias β2i), and LMP7 (alias β5i). [3] The LMP2 protein is composed of 20 amino acids, MECL-1 of 39 amino acids and LMP7 occurs in isoform and therefore can have either 72 or 68 amino acids. [1] The regulatory unit consists of 19 proteins, which are structurally divided into a lid of 9 proteins and a base again of 9 proteins. The RPN10 protein is added to this regulatory complex, which serves to stabilize the structure and as a receptor for ubiquitin. [4]

Function

The function of the immunoproteasome is primarily to specifically cleave proteins into shorter peptides, which can then be displayed on the cell surface together with the MHC I complex. The MHC I complex with bound peptide is then recognized primarily by cytotoxic T cells. In order to expose a peptide on the cell surface, the ubiquitin-labeled protein, specifically cleaved into peptides by immunoproteasome, must first be transferred to the endoplasmic reticulum using TAP1 and TAP2 transporters and chaperones. In the endoplasmic reticulum, the peptide is then bound to an MHC I molecule.

The aforementioned LMP2 and LMP7 subunits are encoded by the PSMB9 (LMP2) and PSMB8 (LMP7) genes, which are found in the MHC II gene cluster of the TAP-1 and TAP-2 genes. [2] The LMP2 subunit has the function of chymotrypsin, which means that it cleaves bonds after hydrophobic substances and this prepares peptides with hydrophobic C anchors for the MHC I complex. While LMP7 and MECL-1 subunits form the same as the standard proteasome subunits, i.e. trypsin and chymotrypsin activity [1]

Diseases associated with immunoproteasome

The ability to display peptides on the cell surface is essential for the recognition of cell status by immune cells. Its proper function is therefore essential and when it is disrupted, a disease occurs. Some examples where the effect of immunoproteasome on pathology has been confirmed are given below:

Mutations in the PSMB8 gene, which encodes the LMP7 subunit, are involved in a variety of diseases and autoinflammatory disorders, the symptoms of which include skin rash, erythema, spiking fever and lipodystrophy, which are presented since early childhood. These also include Nakajo-Nishimura syndrome, a Japanese autoinflammatory syndrom with lipodystrophy syndrome (JASL) or chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature. This list of syndromes is collectively called proteasome-associated autoinflammatory syndrome. [2]

In Alzheimer's disease, a single nucleotide polymorphisms have been found in the immunoproteasome subunit, which increases the chance of its occurrence. Alzheimer's disease is characterized by the presence of amyloid plaques in which an advanced glycation end product occurs. These advanced glycation end-products are not degraded in the cell and remain in it. It is in amyloid plaques that the active activity of the immunoproteasome is found as a consequence of the cells' efforts to remove plaques. [5]

Related Research Articles

Proteasome Protein complexes which degrade unnecessary or damaged proteins by proteolysis

Proteasomes are protein complexes which degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks peptide bonds. Enzymes that help such reactions are called proteases.

PSMB1 Protein found in humans

Proteasome subunit beta type-1 also known as 20S proteasome subunit beta-6 is a protein that in humans is encoded by the PSMB1 gene. This protein is one of the 17 essential subunits that contributes to the complete assembly of 20S proteasome complex. In particular, proteasome subunit beta type-1, along with other beta subunits, assemble into two heptameric rings and subsequently a proteolytic chamber for substrate degradation. The eukaryotic proteasome recognized degradable proteins, including damaged proteins for protein quality control purpose or key regulatory protein components for dynamic biological processes. An essential function of a modified proteasome, the immunoproteasome, is the processing of class I MHC peptides.

PSMB4 Protein found in humans

Proteasome subunit beta type-4 also known as 20S proteasome subunit beta-7 is a protein that in humans is encoded by the PSMB4 gene.

PSMD13 Enzyme found in humans

26S proteasome non-ATPase regulatory subunit 13 is an enzyme that in humans is encoded by the PSMD13 gene.

PSMB10 Protein found in humans

Proteasome subunit beta type-10 as known as 20S proteasome subunit beta-2i is a protein that in humans is encoded by the PSMB10 gene.

PSMB2 Protein found in humans

Proteasome subunit beta type-2 also known as 20S proteasome subunit beta-4 is a protein that in humans is encoded by the PSMB2 gene. This protein is one of the 17 essential subunits that contributes to the complete assembly of 20S proteasome complex. In particular, proteasome subunit beta type-2, along with other beta subunits, assemble into two heptameric rings and subsequently a proteolytic chamber for substrate degradation. The eukaryotic proteasome recognized degradable proteins, including damaged proteins for protein quality control purpose or key regulatory protein components for dynamic biological processes. An essential function of a modified proteasome, the immunoproteasome, is the processing of class I MHC peptides.

PSMD12 Enzyme found in humans

26S proteasome non-ATPase regulatory subunit 12 is an enzyme that in humans is encoded by the PSMD12 gene.

PSMB8 Protein found in humans

Proteasome subunit beta type-8 as known as 20S proteasome subunit beta-5i is a protein that in humans is encoded by the PSMB8 gene. This protein is one of the 17 essential subunits that contributes to the complete assembly of 20S proteasome complex. In particular, proteasome subunit beta type-5, along with other beta subunits, assemble into two heptameric rings and subsequently a proteolytic chamber for substrate degradation. This protein contains "Chymotrypsin-like" activity and is capable of cleaving after large hydrophobic residues of peptide. The eukaryotic proteasome recognized degradable proteins, including damaged proteins for protein quality control purpose or key regulatory protein components for dynamic biological processes. The constitutive subunit beta1, beta2, and beta 5 can be replaced by their inducible counterparts beta1i, 2i, and 5i when cells are under the treatment of interferon-γ. The resulting proteasome complex becomes the so-called immunoproteasome. An essential function of the modified proteasome complex, the immunoproteasome, is the processing of numerous MHC class-I restricted T cell epitopes.

PSMB9 Protein found in humans

Proteasome subunit beta type-9 as known as 20S proteasome subunit beta-1i is a protein that in humans is encoded by the PSMB9 gene.

PSMB5 Protein found in humans

Proteasome subunit beta type-5 as known as 20S proteasome subunit beta-5 is a protein that in humans is encoded by the PSMB5 gene. This protein is one of the 17 essential subunits that contributes to the complete assembly of 20S proteasome complex. In particular, proteasome subunit beta type-5, along with other beta subunits, assemble into two heptameric rings and subsequently a proteolytic chamber for substrate degradation. This protein contains "chymotrypsin-like" activity and is capable of cleaving after large hydrophobic residues of peptide. The eukaryotic proteasome recognized degradable proteins, including damaged proteins for protein quality control purpose or key regulatory protein components for dynamic biological processes. An essential function of a modified proteasome, the immunoproteasome, is the processing of class I MHC peptides.

PSMD7 Enzyme found in humans

26S proteasome non-ATPase regulatory subunit 7, also known as 26S proteasome non-ATPase subunit Rpn8, is an enzyme that in humans is encoded by the PSMD7 gene.

PSMA5 Protein found in humans

Proteasome subunit alpha type-5 also known as 20S proteasome subunit alpha-5 is a protein that in humans is encoded by the PSMA5 gene. This protein is one of the 17 essential subunits that contributes to the complete assembly of 20S proteasome complex.

PSMB7 Protein found in humans

Proteasome subunit beta type-7 as known as 20S proteasome subunit beta-2 is a protein that in humans is encoded by the PSMB7 gene.

PSMD11 Enzyme found in humans

26S proteasome non-ATPase regulatory subunit 11 is an enzyme that in humans is encoded by the PSMD11 gene.

PSMB6 Protein found in humans

Proteasome subunit beta type-6 also known as 20S proteasome subunit beta-1 is a protein that in humans is encoded by the PSMB6 gene.

PSMD9 Enzyme found in humans

26S proteasome non-ATPase regulatory subunit 9 is an enzyme that in humans is encoded by the PSMD9 gene.

PSMD3 Enzyme found in humans

26S proteasome non-ATPase regulatory subunit 3 is an enzyme that in humans is encoded by the PSMD3 gene.

Nakajo syndrome Medical condition

Nakajo syndrome, also called nodular erythema with digital changes, is a rare autosomal recessive congenital disorder first reported in 1939 by A. Nakajo in the offspring of consanguineous parents. The syndrome can be characterized by erythema, loss of body fat in the upper part of the body, and disproportionately large eyes, ears, nose, lips, and fingers.

Autoinflammatory diseases (AIDs) are a group of rare disorders caused by a dysfunction of the innate immune system.They are characterised by a perdiodic or chronic systemic inflammation usually without the involvement of adaptive immunity.

Thymoproteasome is a special kind of proteasome, which is present in vertebrates. In the body it is located in thymus, exclusively in cortical thymic epithelial cells (cTECs). But in thymus we can also find another type of specific proteasome, immunoproteasome, which is present in thymocytes, dendritic cells and medular thymic epithelial cells. It was first described in 2007 during a search for non-intronic sequence proximal to PSMB5 locus in mouse genome. The PSMB5 locus encodes the standard β5 proteasome subunit, while this sequence encodes a variant subunit β5t (PSMB11) specific to thymoproteasome. The importance of this protein complex is its involvement in positive selection of T cells.

References

  1. 1 2 3 Ferrington DA, Gregerson DS (2012). "Immunoproteasomes: structure, function, and antigen presentation". Progress in Molecular Biology and Translational Science. Elsevier. 109: 75–112. doi:10.1016/b978-0-12-397863-9.00003-1. ISBN   978-0-12-397863-9. PMC   4405001 . PMID   22727420.
  2. 1 2 3 Murata S, Takahama Y, Kasahara M, Tanaka K (September 2018). "The immunoproteasome and thymoproteasome: functions, evolution and human disease". Nature Immunology. 19 (9): 923–931. doi:10.1038/s41590-018-0186-z. PMID   30104634. S2CID   51970543.
  3. ↑ Basler M, Kirk CJ, Groettrup M (February 2013). "The immunoproteasome in antigen processing and other immunological functions". Current Opinion in Immunology. 25 (1): 74–80. doi:10.1016/j.coi.2012.11.004. PMID   23219269.
  4. ↑ Budenholzer L, Cheng CL, Li Y, Hochstrasser M (November 2017). "Proteasome Structure and Assembly". Journal of Molecular Biology. 429 (22): 3500–3524. doi:10.1016/j.jmb.2017.05.027. PMC   5675778 . PMID   28583440.
  5. ↑ Johnston-Carey HK, Pomatto LC, Davies KJ (2016-07-03). "The Immunoproteasome in oxidative stress, aging, and disease". Critical Reviews in Biochemistry and Molecular Biology. 51 (4): 268–81. doi:10.3109/10409238.2016.1172554. PMC   4968084 . PMID   27098648.
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