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A role for autophagic protein beclin 1 early in lymphocyte development.

ABSTRACT: Autophagy is a highly regulated and evolutionarily conserved process of cellular self-digestion. Recent evidence suggests that this process plays an important role in regulating T cell homeostasis. In this study, we used Rag1(-/-) (recombination activating gene 1(-/-)) blastocyst complementation and in vitro embryonic stem cell differentiation to address the role of Beclin 1, one of the key autophagic proteins, in lymphocyte development. Beclin 1-deficient Rag1(-/-) chimeras displayed a dramatic reduction in thymic cellularity compared with control mice. Using embryonic stem cell differentiation in vitro, we found that the inability to maintain normal thymic cellularity is likely caused by impaired maintenance of thymocyte progenitors. Interestingly, despite drastically reduced thymocyte numbers, the peripheral T cell compartment of Beclin 1-deficient Rag1(-/-) chimeras is largely normal. Peripheral T cells displayed normal in vitro proliferation despite significantly reduced numbers of autophagosomes. In addition, these chimeras had greatly reduced numbers of early B cells in the bone marrow compared with controls. However, the peripheral B cell compartment was not dramatically impacted by Beclin 1 deficiency. Collectively, our results suggest that Beclin 1 is required for maintenance of undifferentiated/early lymphocyte progenitor populations. In contrast, Beclin 1 is largely dispensable for the initial generation and function of the peripheral T and B cell compartments. This indicates that normal lymphocyte development involves Beclin 1-dependent, early-stage and distinct, Beclin 1-independent, late-stage processes.

SUBMITTER: Arsov I

PROVIDER: S-EPMC3070473 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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A role for autophagic protein beclin 1 early in lymphocyte development.

Arsov Ivica I Adebayo Adeola A Kucerova-Levisohn Martina M Haye Joanna J MacNeil Margaret M Papavasiliou F Nina FN Yue Zhenyu Z Ortiz Benjamin D BD

Journal of immunology (Baltimore, Md. : 1950) 20110114 4

Autophagy is a highly regulated and evolutionarily conserved process of cellular self-digestion. Recent evidence suggests that this process plays an important role in regulating T cell homeostasis. In this study, we used Rag1(-/-) (recombination activating gene 1(-/-)) blastocyst complementation and in vitro embryonic stem cell differentiation to address the role of Beclin 1, one of the key autophagic proteins, in lymphocyte development. Beclin 1-deficient Rag1(-/-) chimeras displayed a dramatic ...[more]

PMID: 21239722

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Project description:Right ventricular structure and function is a major predictor of outcomes in pulmonary hypertension (PH), yet the underlying mechanisms remain poorly understood. Growing evidence suggests the importance of autophagy in cardiac remodeling; however, its dynamics in the process of right ventricle(RV) remodeling in PH has not been fully explored. We sought to study the time course of cardiomyocyte autophagy in the RV in PH and determine whether mammalian target of rapamycin (mTOR) and Beclin-1 hypoxia-related pro-autophagic pathways are underlying mechanisms.Rats were studied at 2, 4, and 6 weeks after subcutaneous injection of 60 mg/kg monocrotaline (MCT) (MCT-2 W, 4 W, 6 W) or vehicle (CON-2 W, 4 W, 6 W). Cardiac hemodynamics and RV function were assessed in rats. Autophagy structures and markers were assessed using transmission electron microscope, RT-qPCR, immunohistochemistry staining, and western blot analyses. Western blot was also used to quantify the expression of mTOR and Beclin-1 mediated pro-autophagy signalings in the RV.Two weeks after MCT injection, pulmonary artery systolic pressure increased and mild RV hypertrophy without RV dilation was observed. RV enlargement presented at 4 weeks with moderately decreased function, whereas typical characteristics of RV decompensation and failure occurred at 6 weeks thus demonstrating the progression of RV remodeling in the MCT model. A higher LC3 (microtubule- associated protein light chain 3) II/I ratio, upregulated LC3 mRNA and protein levels, as well as accumulation of autophagosomes in RV of MCT rats indicated autophagy induction. Autophagy activation was coincident with increased pulmonary artery systolic pressure. Pro-autophagy signaling pathways were activated in a RV remodeling stage-dependent manner since phospho-AMPK (adenosine monophosphate-activated protein kinase)-? were primarily upregulated and phospho-mTOR suppressed in the RV at 2 and 4 weeks post-MCT injection, whearas, BNIP3 (Bcl2-interacting protein 3) and beclin-1 expression were relatively low during these stages, they were significantly upregulated after 6 weeks in this model.Our findings provide evidence of sustained activation of autophagy in RV remodeling of MCT induced PH model, while pro-autophagic signaling pathways varied depending on the phase.

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A role for autophagic protein beclin 1 early in lymphocyte development.

Publications

A role for autophagic protein beclin 1 early in lymphocyte development.

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