mTORC1 activation in B cells confers impairment of marginal zone microarchitecture by exaggerating cathepsin activity

Naresh Kumar Meena, Shakti Prasad Pattanayak, Yael Ben-Nun, Sandrine Benhamron, Saran Kumar, Emmanuelle Merquiol, Nadine Hövelmeyer, Galia Blum*, Boaz Tirosh

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Mammalian target of rapamycin complex 1 (mTORC1) is a key regulator of cell metabolism and lymphocyte proliferation. It is inhibited by the tuberous sclerosis complex (TSC), a heterodimer of TSC1 and TSC2. Deletion of either gene results in robust activation of mTORC1. Mature B cells reside in the spleen at two major anatomical locations, the marginal zone (MZ) and follicles. The MZ constitutes the first line of humoral response against blood-borne pathogens and undergoes atrophy in chronic inflammation. In previous work, we showed that mice deleted for TSC1 in their B cells (TSC1BKO) have almost no MZ B cells, whereas follicular B cells are minimally affected. To explore potential underlying mechanisms for MZ B-cell loss, we have analysed the spleen MZ architecture of TSC1BKO mice and found it to be severely impaired. Examination of lymphotoxins (LTα and LTβ) and lymphotoxin receptor (LTβR) expression indicated that LTβR levels in spleen stroma were reduced by TSC1 deletion in the B cells. Furthermore, LTα transcripts in B cells were reduced. Because LTβR is sensitive to proteolysis, we analysed cathepsin activity in TSC1BKO. A higher cathepsin activity, particularly of cathepsin B, was observed, which was reduced by mTORC1 inhibition with rapamycin in vivo. Remarkably, in vivo administration of a pan-cathepsin inhibitor restored LTβR expression, LTα mRNA levels and the MZ architecture. Our data identify a novel connection, although not elucidated at the molecular level, between mTORC1 and cathepsin activity in a manner relevant to MZ dynamics.

Original languageAmerican English
Pages (from-to)505-518
Number of pages14
JournalImmunology
Volume155
Issue number4
DOIs
StatePublished - Dec 2018

Bibliographical note

Funding Information:
Research was funded by grants from the David R. Bloom Centre for Pharmacy, and the Dr Adolph and Klara Brettler Centre for Research in Pharmacology, Israeli Cancer Association, the Israel Science Foundation (grant 696/14) to BT and the Fritz Thyssen Foundation to BT and NH; and the Israeli National Nanotechnology Initiative for a Focal Technology Area to GB. SPP was supported by the PBC Programme of the higher committee of planning and budgeting of the Israeli council for higher education.

Publisher Copyright:
© 2018 John Wiley & Sons Ltd

Keywords

  • activity based probes
  • cathepsins
  • lymphotoxins
  • mTOR
  • marginal zone

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