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Immunoproteasome assembly: cooperative incorporation of interferon gamma (IFN-gamma)-inducible subunits.

Griffin TA, Nandi D, Cruz M, Fehling HJ, Kaer LV, Monaco JJ, Colbert RA - J. Exp. Med. (1998)

Bottom Line: We demonstrate that MECL requires LMP2 for efficient incorporation into preproteasomes, and preproteasomes containing LMP2 and MECL require LMP7 for efficient maturation.The latter effect depends on the presequence of LMP7, but not on LMP7 catalytic activity.This cooperative mechanism favors the assembly of homogeneous "immunoproteasomes" containing all three inducible subunits, suggesting that these subunits act in concert to enhance proteasomal generation of major histocompatibility complex class I-binding peptides.

View Article: PubMed Central - PubMed

Affiliation: William S. Rowe Division of Rheumatology, Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.

ABSTRACT
LMP2, LMP7, and MECL are interferon gamma-inducible catalytic subunits of vertebrate 20S proteasomes, which can replace constitutive catalytic subunits (delta, X, and Z, respectively) during proteasome biogenesis. We demonstrate that MECL requires LMP2 for efficient incorporation into preproteasomes, and preproteasomes containing LMP2 and MECL require LMP7 for efficient maturation. The latter effect depends on the presequence of LMP7, but not on LMP7 catalytic activity. This cooperative mechanism favors the assembly of homogeneous "immunoproteasomes" containing all three inducible subunits, suggesting that these subunits act in concert to enhance proteasomal generation of major histocompatibility complex class I-binding peptides.

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Cooperative model for proteasome assembly. One major  pathway leads to immunoproteasomes containing all three IFN-γ–inducible catalytic β subunits (LMP2, LMP7, and MECL). Another major  pathway leads to constitutive proteasomes containing all three constitutive  catalytic β subunits (delta [δ], X, and Z). Minor pathways lead to mixed  proteasomes containing assortments of both inducible and constitutive  catalytic subunits. Appendages represent removable presequences. Subunit positions are based on the structure of the yeast 20S proteasome and  assume that inducible subunits occupy the same sites as their constitutive  homologues (3).
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Figure 6: Cooperative model for proteasome assembly. One major pathway leads to immunoproteasomes containing all three IFN-γ–inducible catalytic β subunits (LMP2, LMP7, and MECL). Another major pathway leads to constitutive proteasomes containing all three constitutive catalytic β subunits (delta [δ], X, and Z). Minor pathways lead to mixed proteasomes containing assortments of both inducible and constitutive catalytic subunits. Appendages represent removable presequences. Subunit positions are based on the structure of the yeast 20S proteasome and assume that inducible subunits occupy the same sites as their constitutive homologues (3).

Mentions: Based on our results, we propose a cooperative model for immunoproteasome assembly (Fig. 6). When both IFN-γ–inducible and constitutive catalytic β subunits are synthesized, either pre-LMP2 and pre-MECL are cooperatively incorporated early into preproteasomes or, alternatively, pre-Z is incorporated early. The relative levels of pre-LMP2 and pre-MECL compared to pre-Z may determine which major pathway is favored (33), although differences in affinity of each of these precursor subunits for preproteasomes could also be important. Nevertheless, preproteasomes containing pre-LMP2 and pre-MECL favor the incorporation of LMP7, since these preproteasomes do not efficiently mature when LMP7 is absent and its homologue X is present. This cooperative incorporation of LMP7 into preproteasomes containing pre-LMP2 and pre-MECL leads to 20S immunoproteasomes containing all three IFN-γ–inducible subunits. Cooperative incorporation of constitutive catalytic subunits may also occur, with preproteasomes containing pre-Z favoring the subsequent incorporation of delta and X. Exclusion of X from the immunoproteasome pathway may increase its availability for incorporation into constitutive proteasomes. Evidence supporting this comes from Gaczynska et al. who have shown that overexpression of X increases the content of delta and decreases the content of LMP2 in proteasomes (18). Despite cooperativity, some mixed proteasomes may form, since LMP7 can be incorporated into proteasomes in the absence of LMP2.


Immunoproteasome assembly: cooperative incorporation of interferon gamma (IFN-gamma)-inducible subunits.

Griffin TA, Nandi D, Cruz M, Fehling HJ, Kaer LV, Monaco JJ, Colbert RA - J. Exp. Med. (1998)

Cooperative model for proteasome assembly. One major  pathway leads to immunoproteasomes containing all three IFN-γ–inducible catalytic β subunits (LMP2, LMP7, and MECL). Another major  pathway leads to constitutive proteasomes containing all three constitutive  catalytic β subunits (delta [δ], X, and Z). Minor pathways lead to mixed  proteasomes containing assortments of both inducible and constitutive  catalytic subunits. Appendages represent removable presequences. Subunit positions are based on the structure of the yeast 20S proteasome and  assume that inducible subunits occupy the same sites as their constitutive  homologues (3).
© Copyright Policy
Related In: Results  -  Collection

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Figure 6: Cooperative model for proteasome assembly. One major pathway leads to immunoproteasomes containing all three IFN-γ–inducible catalytic β subunits (LMP2, LMP7, and MECL). Another major pathway leads to constitutive proteasomes containing all three constitutive catalytic β subunits (delta [δ], X, and Z). Minor pathways lead to mixed proteasomes containing assortments of both inducible and constitutive catalytic subunits. Appendages represent removable presequences. Subunit positions are based on the structure of the yeast 20S proteasome and assume that inducible subunits occupy the same sites as their constitutive homologues (3).
Mentions: Based on our results, we propose a cooperative model for immunoproteasome assembly (Fig. 6). When both IFN-γ–inducible and constitutive catalytic β subunits are synthesized, either pre-LMP2 and pre-MECL are cooperatively incorporated early into preproteasomes or, alternatively, pre-Z is incorporated early. The relative levels of pre-LMP2 and pre-MECL compared to pre-Z may determine which major pathway is favored (33), although differences in affinity of each of these precursor subunits for preproteasomes could also be important. Nevertheless, preproteasomes containing pre-LMP2 and pre-MECL favor the incorporation of LMP7, since these preproteasomes do not efficiently mature when LMP7 is absent and its homologue X is present. This cooperative incorporation of LMP7 into preproteasomes containing pre-LMP2 and pre-MECL leads to 20S immunoproteasomes containing all three IFN-γ–inducible subunits. Cooperative incorporation of constitutive catalytic subunits may also occur, with preproteasomes containing pre-Z favoring the subsequent incorporation of delta and X. Exclusion of X from the immunoproteasome pathway may increase its availability for incorporation into constitutive proteasomes. Evidence supporting this comes from Gaczynska et al. who have shown that overexpression of X increases the content of delta and decreases the content of LMP2 in proteasomes (18). Despite cooperativity, some mixed proteasomes may form, since LMP7 can be incorporated into proteasomes in the absence of LMP2.

Bottom Line: We demonstrate that MECL requires LMP2 for efficient incorporation into preproteasomes, and preproteasomes containing LMP2 and MECL require LMP7 for efficient maturation.The latter effect depends on the presequence of LMP7, but not on LMP7 catalytic activity.This cooperative mechanism favors the assembly of homogeneous "immunoproteasomes" containing all three inducible subunits, suggesting that these subunits act in concert to enhance proteasomal generation of major histocompatibility complex class I-binding peptides.

View Article: PubMed Central - PubMed

Affiliation: William S. Rowe Division of Rheumatology, Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.

ABSTRACT
LMP2, LMP7, and MECL are interferon gamma-inducible catalytic subunits of vertebrate 20S proteasomes, which can replace constitutive catalytic subunits (delta, X, and Z, respectively) during proteasome biogenesis. We demonstrate that MECL requires LMP2 for efficient incorporation into preproteasomes, and preproteasomes containing LMP2 and MECL require LMP7 for efficient maturation. The latter effect depends on the presequence of LMP7, but not on LMP7 catalytic activity. This cooperative mechanism favors the assembly of homogeneous "immunoproteasomes" containing all three inducible subunits, suggesting that these subunits act in concert to enhance proteasomal generation of major histocompatibility complex class I-binding peptides.

Show MeSH
Related in: MedlinePlus