Bmf Facilitates Protein Degradation and Reduces Beclin1 Ubiquitination to Inhibit Autophagy Independent of mTOR
Delgado-Vergas, M.; Fort, S.; Tassew, D.; Tesfaigzi, Y.
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Previous observations suggested that Bcl-2 modifying factor (Bmf) affects autophagy but the underlying mechanisms were unknown. The present studies show that Bmf inhibited the initiation and flux of autophagy in a manner that is independent of the mTOR pathway and inhibition of mTOR increased Bmf expression to temper the autophagic cell death. In mice, emphysema was observed in Bmf-deficient mice, suggesting that Bmf suppresses autophagic cell death of alveolar type II cells. Bmf deficiency increased ubiquitination of Beclin1 with K63 chains and released Beclin1 from Bcl-2. However, Bmf deficiency also increased the levels of polyubiquitinated proteins in general. In mice, Bmf-deficiency robustly increased p62 levels in all tissues analyzed, but LC3-II levels were reduced only in the hearts of old mice. Also, Bmf-deficiency caused persistent mucous cell metaplasia in mice exposed to allergen and increased levels of polyubiquitinated Muc5ac in differentiated airway epithelial cells. The reduction of ubiquitinated proteins was mediated by the BH3- and dynein binding-domains of Bmf. Together, these findings show that the primary role of Bmf is to reduce protein levels and affects K63- and K48-ubiqutination.
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