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Non-apoptotic Fas signaling controls CD40 dependent mTOR activation and human B cell fate via PTEN nuclear exclusion

ABSTRACT: Defective Fas signaling causes autoimmune lymphoproliferative syndrome (ALPS). While defective apoptosis may impair negative selection and removal of autoreactive B lymphocytes, Fas transmits also non-apoptotic signals. We show herethat transient Fas ligation in CD40L-stimulated human B cells specifically decreased the mTOR axis activation without causing apoptosis. This signal modulation was absent in ALPS patients. Rather, mTOR signaling was enhanced in germinal center (GC) B cells and plasmablasts derived from a ALPS patient lymph node . Mechanistically, transient Fas engagement induced recruitment of DAXX to the activated Fas complex and nuclear exclusion of PTEN. Likewise, Fas stimulation promoted expression of transcripts like MYC and CXCR4, that regulate GC formation and fate decisions of established GC B cells. We suggest that non-apoptotic Fas signaling has a physiological impact on activated B cell fate decisions explaining the effectiveness of mTOR inhibitors in the treatment of ALPS autoimmunity.

INSTRUMENT(S): LTQ Orbitrap Velos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Blood Cell, Naive B Cell, Blood

DISEASE(S): Autoimmune Lymphoproliferative Syndrome

SUBMITTER: Marta Rizzi

LAB HEAD: Marta Rizzi

PROVIDER: PXD017601 | Pride | 2024-04-08

REPOSITORIES: Pride

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			Action	DRS
	CD40L-1-CYT.raw	Raw
	CD40L-1-MB.raw	Raw
	CD40L-1-NUC.raw	Raw
	CD40L-1-ORG.raw	Raw
	CD40L-1_CYT.mgf	Mgf

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