Context-Specific BAFF-R Signaling by the NF-κB and PI3K Pathways

Julia Jellusova; Ana V. Miletic; Matthew H. Cato; Wai Wai Lin; Yinling Hu; Gail A. Bishop; Mark J. Shlomchik; Robert C. Rickert

doi:10.1016/j.celrep.2013.10.022

Context-Specific BAFF-R Signaling by the NF-κB and PI3K Pathways

Julia Jellusova, Ana V. Miletic, Matthew H. Cato, Wai Wai Lin, Yinling Hu, Gail A. Bishop, Mark J. Shlomchik, Robert C. Rickert

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

71 Scopus citations

Abstract

BAFF is a soluble factor required for B cell maturation and survival. BAFF-R signals via the noncanonical NF-κB pathway regulated by the TRAF3/NIK/IKK1 axis. We show that deletion of Ikk1 during early B cell development causes a partial impairment in B cell maturation and BAFF-dependent survival, but inactivation of Ikk1 in mature B cells does not affect survival. We further show that BAFF-R employs CD19 to promote survival via phosphatidylinositol 3-kinase (PI3K), and that coinactivation of Cd19 and Ikk1 causes a profound block in B cell maturation at the transitional stage. Consistent with a role for PI3K in BAFF-R function, inactivation of PTEN mediates a partial rescue of B cell maturation and function in Baff^-/- animals. Elevated PI3K signaling also circumvents BAFF-dependent survival in a spontaneous B cell lymphoma model. These findings indicate that the combined activities of PI3K and IKK1 drive peripheral B cell differentiation and survival in a context-dependent manner

Original language	English
Pages (from-to)	1022-1035
Number of pages	14
Journal	Cell Reports
Volume	5
Issue number	4
DOIs	https://doi.org/10.1016/j.celrep.2013.10.022
State	Published - 27 Nov 2013
Externally published	Yes

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@article{f9191d1611714787bc2ceee5688ea568,

title = "Context-Specific BAFF-R Signaling by the NF-κB and PI3K Pathways",

abstract = "BAFF is a soluble factor required for B cell maturation and survival. BAFF-R signals via the noncanonical NF-κB pathway regulated by the TRAF3/NIK/IKK1 axis. We show that deletion of Ikk1 during early B cell development causes a partial impairment in B cell maturation and BAFF-dependent survival, but inactivation of Ikk1 in mature B cells does not affect survival. We further show that BAFF-R employs CD19 to promote survival via phosphatidylinositol 3-kinase (PI3K), and that coinactivation of Cd19 and Ikk1 causes a profound block in B cell maturation at the transitional stage. Consistent with a role for PI3K in BAFF-R function, inactivation of PTEN mediates a partial rescue of B cell maturation and function in Baff-/- animals. Elevated PI3K signaling also circumvents BAFF-dependent survival in a spontaneous B cell lymphoma model. These findings indicate that the combined activities of PI3K and IKK1 drive peripheral B cell differentiation and survival in a context-dependent manner",

author = "Julia Jellusova and Miletic, {Ana V.} and Cato, {Matthew H.} and Lin, {Wai Wai} and Yinling Hu and Bishop, {Gail A.} and Shlomchik, {Mark J.} and Rickert, {Robert C.}",

note = "Funding Information: We thank the members of the Rickert laboratory for discussions, and Dr. D. Nemazee (TSRI, La Jolla, CA) for facilitating the transfer of the Baff −/− mice. This work was supported by NIH grants AI041649, HL088686, and RR026280 (to R.C.R); AI043603 and AR44077 (to M.J.S.); and AI49993 (to G.A.B). G.A.B. received resources and use of facilities from the Iowa City VAMC. A.V.M. was supported by NIH F32 fellowship CA132350. J.J. was supported by fellowships from the Deutsche Forschungsgemeinschaft and the Arthritis National Research Foundation. ",

year = "2013",

month = nov,

day = "27",

doi = "10.1016/j.celrep.2013.10.022",

language = "English",

volume = "5",

pages = "1022--1035",

journal = "Cell Reports",

issn = "2211-1247",

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number = "4",

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T1 - Context-Specific BAFF-R Signaling by the NF-κB and PI3K Pathways

AU - Jellusova, Julia

AU - Miletic, Ana V.

AU - Cato, Matthew H.

AU - Lin, Wai Wai

AU - Hu, Yinling

AU - Bishop, Gail A.

AU - Shlomchik, Mark J.

AU - Rickert, Robert C.

N1 - Funding Information: We thank the members of the Rickert laboratory for discussions, and Dr. D. Nemazee (TSRI, La Jolla, CA) for facilitating the transfer of the Baff −/− mice. This work was supported by NIH grants AI041649, HL088686, and RR026280 (to R.C.R); AI043603 and AR44077 (to M.J.S.); and AI49993 (to G.A.B). G.A.B. received resources and use of facilities from the Iowa City VAMC. A.V.M. was supported by NIH F32 fellowship CA132350. J.J. was supported by fellowships from the Deutsche Forschungsgemeinschaft and the Arthritis National Research Foundation.

PY - 2013/11/27

Y1 - 2013/11/27

N2 - BAFF is a soluble factor required for B cell maturation and survival. BAFF-R signals via the noncanonical NF-κB pathway regulated by the TRAF3/NIK/IKK1 axis. We show that deletion of Ikk1 during early B cell development causes a partial impairment in B cell maturation and BAFF-dependent survival, but inactivation of Ikk1 in mature B cells does not affect survival. We further show that BAFF-R employs CD19 to promote survival via phosphatidylinositol 3-kinase (PI3K), and that coinactivation of Cd19 and Ikk1 causes a profound block in B cell maturation at the transitional stage. Consistent with a role for PI3K in BAFF-R function, inactivation of PTEN mediates a partial rescue of B cell maturation and function in Baff-/- animals. Elevated PI3K signaling also circumvents BAFF-dependent survival in a spontaneous B cell lymphoma model. These findings indicate that the combined activities of PI3K and IKK1 drive peripheral B cell differentiation and survival in a context-dependent manner

AB - BAFF is a soluble factor required for B cell maturation and survival. BAFF-R signals via the noncanonical NF-κB pathway regulated by the TRAF3/NIK/IKK1 axis. We show that deletion of Ikk1 during early B cell development causes a partial impairment in B cell maturation and BAFF-dependent survival, but inactivation of Ikk1 in mature B cells does not affect survival. We further show that BAFF-R employs CD19 to promote survival via phosphatidylinositol 3-kinase (PI3K), and that coinactivation of Cd19 and Ikk1 causes a profound block in B cell maturation at the transitional stage. Consistent with a role for PI3K in BAFF-R function, inactivation of PTEN mediates a partial rescue of B cell maturation and function in Baff-/- animals. Elevated PI3K signaling also circumvents BAFF-dependent survival in a spontaneous B cell lymphoma model. These findings indicate that the combined activities of PI3K and IKK1 drive peripheral B cell differentiation and survival in a context-dependent manner

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DO - 10.1016/j.celrep.2013.10.022

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VL - 5

SP - 1022

EP - 1035

JO - Cell Reports

JF - Cell Reports

IS - 4

ER -

Context-Specific BAFF-R Signaling by the NF-κB and PI3K Pathways

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