Calcium-Modulating Cyclophilin Ligand Is Essential for the Survival of Activated T Cells and for Adaptive Immunity

Chan, Siaw Li; Lindquist, Lonn D.; Hansen, Michael J.; Girtman, Megan A.; Pease, Larry R.; Bram, Richard J.

doi:10.4049/jimmunol.1500308

Cited by 7 publications

(11 citation statements)

References 38 publications

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“…13,14,15,17 Under conditional Caml deletion, these cell types showed increased apoptosis when they were activated by mitogens, similar to our results in Eμ-Myc lymphomas. Notably, CAML does not appear to function as a constitutive survival factor, because unstimulated cells (that is, thymocytes, mature B and T cells) did not activate apoptosis.…”

Section: Discussionsupporting

confidence: 89%

“…2 Although the Eμ-Myc cells in this study were not stimulated by exogenous factors, they exhibited rapid, basal growth, suggesting that proliferation of differentiated cells is necessary for detecting CAML-related phenotypes. The recent finding that rapamycin rescues CAML-deficient T lymphocytes from cytotoxicity by preventing cell division, 17 aligns with our lymphoma model showing that Caml -deleted Eμ-Myc cells arrest in G2/M. Therefore, we reason that CAML facilitates cell cycle progression, which is apparent when cells are actively proliferating.…”

Section: Discussionsupporting

confidence: 88%

“…Western blotting indicated CAML protein reduction in tumors due to tamoxifen treatment (Figure 3c), similar to that previously demonstrated in tissues examined for Cre-ER ; Caml fl/fl mice treated with tamoxifen. 14,17 Kaplan–Meier survival curves plotted for tumor end points requiring killing showed a dramatic difference in survival with the vast majority of tamoxifen-treated mice alive at the conclusion of the experiment ( P <0.01; Figure 3d). We conclude that CAML is essential for Myc-dependent lymphoma growth and survival in vivo .…”

Section: Resultsmentioning

confidence: 99%

“…Notably, CAML does not appear to function as a constitutive survival factor, because unstimulated cells (that is, thymocytes, mature B and T cells) did not activate apoptosis. 13,15,17 Furthermore, embryonic stem cells prepared from Caml −/− embryos were normal and proliferated rapidly. 2 Although the Eμ-Myc cells in this study were not stimulated by exogenous factors, they exhibited rapid, basal growth, suggesting that proliferation of differentiated cells is necessary for detecting CAML-related phenotypes.…”

Section: Discussionmentioning

confidence: 98%

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CAML mediates survival of Myc-induced lymphoma cells independent of tail-anchored protein insertion

et al. 2017

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Calcium-modulating cyclophilin ligand (CAML) is an endoplasmic reticulum (ER) protein that functions, along with WRB and TRC40, to mediate tail-anchored (TA) protein insertion into the ER membrane. Physiologic roles for CAML include endocytic trafficking, intracellular calcium signaling, and the survival and proliferation of specialized immune cells, recently attributed to its requirement for TA protein insertion. To identify a possible role for CAML in cancer cells, we generated Eμ-Myc transgenic mice that carry a tamoxifen-inducible deletion allele of Caml. In multiple B-cell lymphoma cell lines derived from these mice, homozygous loss of Caml activated apoptosis. Cell death was blocked by Bcl-2/Bcl-xL overexpression; however, rescue from apoptosis was insufficient to restore proliferation. Tumors established from an Eμ-Myc lymphoma cell line completely regressed after tamoxifen administration, suggesting that CAML is also required for these cancer cells to survive and grow in vivo. Cell cycle analyses of Caml-deleted lymphoma cells revealed an arrest in G2/M, accompanied by low expression of the mitotic marker, phospho-histone H3 (Ser10). Surprisingly, lymphoma cell viability did not depend on the domain of CAML required for its interaction with TRC40. Furthermore, a small protein fragment consisting of the C-terminal 111 amino acid residues of CAML, encompassing the WRB-binding domain, was sufficient to rescue growth and survival of Caml-deleted lymphoma cells. Critically, this minimal region of CAML did not restore TA protein insertion in knockout cells. Taken together, these data reveal an essential role for CAML in supporting survival and mitotic progression in Myc-driven lymphomas that is independent of its TA protein insertion function.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionsupporting

confidence: 88%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 98%

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CAML mediates survival of Myc-induced lymphoma cells independent of tail-anchored protein insertion

et al. 2017

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“…Indeed, although our coprecipitation experiments with anti-CAML antibodies demonstrated that WRB is quantitatively associated with CAML, we could not carry out the reverse experiment, because there are currently no available antibodies that immunoprecipitate native WRB. It is possible that some of the many functions linked to CAML, including signal transduction (41,42), immune cell survival (26), membrane traffic (24,43), and chromosome segregation (44), are independent from its role in TA protein insertion and could be carried out by a pool of WRB-free CAML. In addition, or alternatively, the excess CAML could increase the efficiency of recruitment of TRC40-TA complexes to the ER membrane, handing them over to the CAML-WRB complex.…”

Section: Discussionmentioning

confidence: 99%

Tail-anchored Protein Insertion in Mammals

Colombo

Cardani

Maroli

et al. 2016

Journal of Biological Chemistry

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The GET (guided entry of tail-anchored proteins)/TRC (transmembrane recognition complex) pathway for tail-anchored protein targeting to the endoplasmic reticulum (ER) has been characterized in detail in yeast and is thought to function similarly in mammals, where the orthologue of the central ATPase, Get3, is known as TRC40 or Asna1. Get3/TRC40 function requires an ER receptor, which in yeast consists of the Get1/ Get2 heterotetramer and in mammals of the WRB protein (tryptophan-rich basic protein), homologous to yeast Get1, in combination with CAML (calcium-modulating cyclophilin ligand), which is not homologous to Get2. To better characterize the mammalian receptor, we investigated the role of endogenous WRB and CAML in tail-anchored protein insertion as well as their association, concentration, and stoichiometry in rat liver microsomes and cultured cells. Functional proteoliposomes, reconstituted from a microsomal detergent extract, lost their activity when made with an extract depleted of TRC40-associated proteins or of CAML itself, whereas in vitro synthesized CAML and WRB together were sufficient to confer insertion competence to liposomes. CAML was found to be in ϳ5-fold excess over WRB, and alteration of this ratio did not inhibit insertion. Depletion of each subunit affected the levels of the other one; in the case of CAML silencing, this effect was attributable to destabilization of the WRB transcript and not of WRB protein itself. These results reveal unanticipated complexity in the mutual regulation of the TRC40 receptor subunits and raise the question as to the role of the excess CAML in the mammalian ER.Whereas most membrane proteins are targeted to the endoplasmic reticulum (ER) 3 by the signal recognition particle-dependent co-translational mechanism (1, 2), tail-anchored (TA) membrane proteins are inserted into all their target membranes, including the ER, by post-translational pathways (for review see Refs. 3-5). The inability of TA proteins to utilize the co-translational route is due to the location of their sole targeting determinant, the transmembrane domain (TMD), at their extreme C terminus, such that it becomes accessible to cytosolic targeting factors only after release of the completed polypeptide chain from the ribosome. Because TA proteins are numerous (6), play fundamental physiological roles (e.g. as SNAREs and apoptosis regulating factors; Ref.3), and are present in all domains of life (7), a great deal of research has been dedicated to the elucidation of the mechanisms by which they reach and insert into their target membranes. On the basis of studies in cell-free mammalian systems (8, 9) and of in vitro and in vivo investigations in yeast (10), a novel system operating in the delivery of TA proteins to the ER membrane was identified and extensively characterized (for review, see Refs. 11 and 12). This system is centered around a cytosolic P-type ATPase, named Get3 (guided entry of tailanchored proteins) in yeast and TRC40 (transmembrane domain recognition complex subunit of 40...

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Particulate matter in poultry house on poultry respiratory disease: a systematic review

et al. 2023

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Calcium-Modulating Cyclophilin Ligand Is Essential for the Survival of Activated T Cells and for Adaptive Immunity

Cited by 7 publications

References 38 publications

CAML mediates survival of Myc-induced lymphoma cells independent of tail-anchored protein insertion

CAML mediates survival of Myc-induced lymphoma cells independent of tail-anchored protein insertion

Tail-anchored Protein Insertion in Mammals

Particulate matter in poultry house on poultry respiratory disease: a systematic review

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