The Beclin 1 network regulates autophagy and apoptosis

Abstract

Beclin 1, the mammalian orthologue of yeast Atg6, has a central role in autophagy, a process of programmed cell survival, which is increased during periods of cell stress and extinguished during the cell cycle. It interacts with several cofactors (Atg14L, UVRAG, Bif-1, Rubicon, Ambra1, HMGB1, nPIST, VMP1, SLAM, IP 3 R, PINK and survivin) to regulate the lipid kinase Vps-34 protein and promote formation of Beclin 1-Vps34-Vps15 core complexes, thereby inducing autophagy. In contrast, the BH3 domain of Beclin 1 is bound to, and inhibited by Bcl-2 or Bcl-XL. This interaction can be disrupted by phosphorylation of Bcl-2 and Beclin 1, or ubiquitination of Beclin 1. Interestingly, caspase-mediated cleavage of Beclin 1 promotes crosstalk between apoptosis and autophagy. Beclin 1 dysfunction has been implicated in many disorders, including cancer and neurodegeneration. Here, we summarize new findings regarding the organization and function of the Beclin 1 network in cellular homeostasis, focusing on the cross-regulation between apoptosis and autophagy. Cell Death and Differentiation (2011) 18, 571-580; doi:10.1038/cdd.2010 published online 11 February 2011 Autophagy is an essential process that consists of selective degradation of cellular components. There are at least three different types of autophagy described and possibly more. These autophagy types include macroautophagy (hereafter referred to as autophagy), microautophagy and chaperonemediated autophagy. 1 The initial step of autophagy is the surrounding and sequestering of cytoplasmic organelles and proteins within an isolation membrane (phagophore). Potential sources for the membrane to generate the phagophore include the Golgi complex, endosomes, the endoplasmic reticulum (ER), mitochondria and the plasma membrane. 2 The nascent membranes are fused at their edges to form double-membrane vesicles, called autophagosomes. Autophagosomes undergo a stepwise maturation process, including fusion with acidified endosomal and/or lysosomal vesicles, eventually leading to the delivery of cytoplasmic contents to lysosomal components, where they fuse, then degrade and are recycled (Figure 1a). The process of mammalian autophagy is divided into six principal steps: initiation (Figure 1b It has been well demonstrated that autophagy depends on Atg5/Atg7, is associated with microtubule-associated protein light chain 3 (LC3) truncation and lipidation, and may originate directly from the ER membrane and other membrane organelles. Furthermore, recent study has identified a Atg5/Atg7-independent pathway of autophagy. 3 This pathway of autophagy was not associated with LC3 processing but appeared to involve autophagosome formation from late endosomes and the trans-Golgi. 3 Atg7-independent autophagy had been implicated in mitochondrial clearance from reticulocytes. 4 The exact molecular basis of Atg5/Atg7-independent autophagy remains to be elucidated. Interestingly, Beclin 1 is required for Atg5/Atg7-dependent and -independent autophagy. 3 However, the presence of Beclin 1-indep...

Effect of animal mixing as a stressor on biomarkers of autophagy and oxidative stress during pig muscle maturation

“…TAA = total antioxidant activity; SOD = superoxide dismutase; CAT = catalase; and LC3 ratio = LC3-II/LC3-I; UF-UTL = unmixed at the farm-unmixed during transport and lairage; MF-UTL = mixed at the farm-unmixed during transport and lairage; MF-MTL = mixed at the farm-mixed during transport and lairage; PC = principal component. a central role in autophagy as a main contributor to autophagy initiation (Kang et al, 2011). Its value was even higher in the MF-UTL group (animal mixing at farm) in comparison with the MF-MTL group (animal mixing at farm and during transport and lairage).…”

AC‐1001 H3 CDR peptide induces apoptosis and signs of autophagy in vitro and exhibits antimetastatic activity in a syngeneic melanoma model

“…The endogenous expression of Beclin 1 was high in B16F10‐Nex2 and low in A2058 lysates. In the absence of autophagy Beclin 1 could be bound to Bcl‐2 or Bcl‐XL 21, which are also highly expressed in B16F10 cells 22 (V.S.C. Maia, unpublished result).…”

“…The signs of autophagy clearly precede the apoptosis process as shown by Beclin 1 expression in both B1F10‐Nex2 and A2058 cell lines as well as its degradation simultaneously with caspase 3 expression. Caspase‐mediated cleavage of beclin 1 promotes the crosstalk between apoptosis and autophagy 21.…”

Autophagy enhances the replication of Peste des petits ruminants virus and inhibits caspase-dependent apoptosis in vitro

“…These data indicated that autophagosome formation plays a critical anti-apoptosis role during PPRV infection. Moreover, the expression products of the ATG7 and Beclin-1 genes are essential for the activation of autophagosome formation, and knocking down the ATG7 and Beclin-1 genes can impair the autophagic pathway [70,71]. Interestingly, Beclin-1 is required for ATG7-dependent and ATG7-independent autophagy [72].…”

“…Beclin-1 also regulates apoptosis by interacting with both BCL2 and BCL2L1/BCL-XL [73]. Additionally, apoptosis may inhibit autophagy as CAPN/calpain cleaves ATG5, which triggers CASP-dependent cell death [71,74]. Caspases can also cleave Beclin-1 in apoptosis, thereby destroying its pro-autophagic activity [75].…”