LMP2 immunoproteasome promotes lymphocyte survival by degrading apoptotic BH3-only proteins

Damien Zanker; Kenneth Pang; Sara Oveissi; Chunni Lu; Pierre Faou; Cameron Nowell; George W. Mbogo; Sebastian Carotta; Cathy Quillici; Guna Karupiah; Margaret L. Hibbs; Stephen L. Nutt; Paul Neeson; Hamsa Puthalakath; Weisan Chen

doi:10.1111/imcb.12163

LMP2 immunoproteasome promotes lymphocyte survival by degrading apoptotic BH3-only proteins

Damien Zanker, Kenneth Pang, Sara Oveissi, Chunni Lu, Pierre Faou, Cameron Nowell, George W. Mbogo, Sebastian Carotta, Cathy Quillici, Guna Karupiah, Margaret L. Hibbs, Stephen L. Nutt, Paul Neeson, Hamsa Puthalakath, Weisan Chen^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

4 Citations (Scopus)

Abstract

The role of the immunoproteasome is perceived as confined to adaptive immune responses given its ability to produce peptides ideal for MHC Class-I binding. Here, we demonstrate that the immunoproteasome subunit, LMP2, has functions beyond its immunomodulatory role. Using LMP2-deficient mice, we demonstrate that LMP2 is crucial for lymphocyte development and survival in the periphery. Moreover, LMP2-deficient lymphocytes show impaired degradation of key BH3-only proteins, resulting in elevated levels of pro-apoptotic BIM and increased cell death. Interestingly, LMP2 is the sole immunoproteasome subunit required for BIM degradation. Together, our results suggest LMP2 has important housekeeping functions and represents a viable therapeutic target for cancer.

Original language	English
Pages (from-to)	981-993
Number of pages	13
Journal	Immunology and Cell Biology
Volume	96
Issue number	9
DOIs	https://doi.org/10.1111/imcb.12163
Publication status	Published - Oct 2018
Externally published	Yes

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10.1111/imcb.12163

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title = "LMP2 immunoproteasome promotes lymphocyte survival by degrading apoptotic BH3-only proteins",

abstract = "The role of the immunoproteasome is perceived as confined to adaptive immune responses given its ability to produce peptides ideal for MHC Class-I binding. Here, we demonstrate that the immunoproteasome subunit, LMP2, has functions beyond its immunomodulatory role. Using LMP2-deficient mice, we demonstrate that LMP2 is crucial for lymphocyte development and survival in the periphery. Moreover, LMP2-deficient lymphocytes show impaired degradation of key BH3-only proteins, resulting in elevated levels of pro-apoptotic BIM and increased cell death. Interestingly, LMP2 is the sole immunoproteasome subunit required for BIM degradation. Together, our results suggest LMP2 has important housekeeping functions and represents a viable therapeutic target for cancer.",

keywords = "BIM, LMP2, NFκB, T-cell development, immunoproteasome, lymphocyte differentiation, survival",

author = "Damien Zanker and Kenneth Pang and Sara Oveissi and Chunni Lu and Pierre Faou and Cameron Nowell and Mbogo, {George W.} and Sebastian Carotta and Cathy Quillici and Guna Karupiah and Hibbs, {Margaret L.} and Nutt, {Stephen L.} and Paul Neeson and Hamsa Puthalakath and Weisan Chen",

note = "Publisher Copyright: {\textcopyright} 2018 Australasian Society for Immunology Inc.",

year = "2018",

month = oct,

doi = "10.1111/imcb.12163",

language = "English",

volume = "96",

pages = "981--993",

journal = "Immunology and Cell Biology",

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T1 - LMP2 immunoproteasome promotes lymphocyte survival by degrading apoptotic BH3-only proteins

AU - Zanker, Damien

AU - Pang, Kenneth

AU - Oveissi, Sara

AU - Lu, Chunni

AU - Faou, Pierre

AU - Nowell, Cameron

AU - Mbogo, George W.

AU - Carotta, Sebastian

AU - Quillici, Cathy

AU - Karupiah, Guna

AU - Hibbs, Margaret L.

AU - Nutt, Stephen L.

AU - Neeson, Paul

AU - Puthalakath, Hamsa

AU - Chen, Weisan

PY - 2018/10

Y1 - 2018/10

N2 - The role of the immunoproteasome is perceived as confined to adaptive immune responses given its ability to produce peptides ideal for MHC Class-I binding. Here, we demonstrate that the immunoproteasome subunit, LMP2, has functions beyond its immunomodulatory role. Using LMP2-deficient mice, we demonstrate that LMP2 is crucial for lymphocyte development and survival in the periphery. Moreover, LMP2-deficient lymphocytes show impaired degradation of key BH3-only proteins, resulting in elevated levels of pro-apoptotic BIM and increased cell death. Interestingly, LMP2 is the sole immunoproteasome subunit required for BIM degradation. Together, our results suggest LMP2 has important housekeeping functions and represents a viable therapeutic target for cancer.

AB - The role of the immunoproteasome is perceived as confined to adaptive immune responses given its ability to produce peptides ideal for MHC Class-I binding. Here, we demonstrate that the immunoproteasome subunit, LMP2, has functions beyond its immunomodulatory role. Using LMP2-deficient mice, we demonstrate that LMP2 is crucial for lymphocyte development and survival in the periphery. Moreover, LMP2-deficient lymphocytes show impaired degradation of key BH3-only proteins, resulting in elevated levels of pro-apoptotic BIM and increased cell death. Interestingly, LMP2 is the sole immunoproteasome subunit required for BIM degradation. Together, our results suggest LMP2 has important housekeeping functions and represents a viable therapeutic target for cancer.

KW - BIM

KW - LMP2

KW - NFκB

KW - T-cell development

KW - immunoproteasome

KW - lymphocyte differentiation

KW - survival

UR - http://www.scopus.com/inward/record.url?scp=85055204607&partnerID=8YFLogxK

U2 - 10.1111/imcb.12163

DO - 10.1111/imcb.12163

M3 - Article

SN - 0818-9641

VL - 96

SP - 981

EP - 993

JO - Immunology and Cell Biology

JF - Immunology and Cell Biology

IS - 9

ER -

LMP2 immunoproteasome promotes lymphocyte survival by degrading apoptotic BH3-only proteins

Abstract

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