Beclin 1-independent autophagy induced by a Bcl-X_L/Bcl-2 targeting compound, Z18

Abstract

Inhibitors of Bcl-XL/Bcl-2 can induce autophagy by releasing the autophagic protein Beclin 1 from its complexes with these proteins. Here we report a novel compound targeting the BH3 binding groove of Bcl-XL/Bcl-2, Z18, which efficiently induces autophagy-associated cell death in HeLa cells, without apparent apoptosis. Unexpectedly, the inhibition of Beclin 1 and phosphatidylinositol 3-kinase have no obvious effect on Z18-induced autophagy in HeLa cells, implying that it is a non-canonical Beclin 1-independent autophagy. Meanwhile, the accumulation of autophagosomes is positively correlated with Z18-induced cell death and the full flux of autophagy is not necessary.

Divergent roles of BECN1 in LC3 lipidation and autophagosomal function

“…14,15 Although the suppression of BECN1 impairs the autophagy-associated post-translational processing of LC3-I to LC3-II, [16][17][18] BECN1-independent autophagy has been reported, in which LC3B lipidation fails to respond to BECN1 level. [19][20][21][22][23][24][25][26][27][28][29][30][31][32][33] Notably in yeast cells upon autophagy induction, Atg8 can still be lipidated to form Atg8-PE and exhibit a punctate structure in the absence of Vps30/Atg6, the BECN1 ortholog in yeast. 13,34 It is important therefore to clarify the role of BECN1 in the LC3B lipidation and the overall autophagy function in mammalian cells.…”

Beclin 1 Is Required for Starvation-Enhanced, but Not Rapamycin-Enhanced, LC3-Associated Phagocytosis of Burkholderia pseudomallei in RAW 264.7 Cells

“…Several reports of Beclin 1-independent autophagy pathways have been made recently (17)(18)(19)(20)(21)(22)(23). However, the responsiveness of these pathways to rapamycin has not been addressed.…”

Recombinant protein rVP1 upregulates BECN1-independent autophagy, MAPK1/3 phosphorylation and MMP9 activity via WIPI1/WIPI2 to promote macrophage migration

“…Several studies have indicated that the ATG5 and ATG7 conjugation system is required for LC3-related autophagosome and BECN1-independent autophagy. 10,[12][13][14] To examine whether or not ATG5 and ATG7 are involved in rVP1-mediated BECN1 -independent autophagy, Atg5 and Atg7 were knocked down by siRNA. Our results showed that after knockdown of Atg5 and Atg7, rVP1 was not able to elicit LC3 lipidation in macrophages (Fig.…”

“…7,8 Although BECN1 is crucial for the nucleation step of microtubuleassociated protein 1 light chain 3 (LC3)-related autophagosome synthesis, increasing evidence suggests that certain noncanonical (BECN1-independent) autophagy 9 can be induced independent of BECN1 or PtdIns3K in several cell types by specific stimulants. [10][11][12][13][14][15][16] The antitumor phenols such as resveratrol and gossypol can induce BECN1-independent autophagy. [10][11][12] LC3-related autophagosome formation requires ATG5 and ATG7, whereas certain autophagosomes may result from late endosomes and the trans-Golgi without participation of ATG5, ATG7 and LC3 processing.…”