An insight into the mechanistic role of Beclin 1 and its inhibition by prosurvival Bcl-2 family proteins

Autophagy. 2008 May;4(4):519-20. doi: 10.4161/auto.5846. Epub 2008 Mar 6.

Abstract

A multiprotein complex composed of Beclin 1, PI(3)KC3 and UVRAG promotes autophagosome formation, while this activity is suppressed by a cohort of antiapoptotic Bcl-2 family members. Recently, we showed that a viral Bcl-2 of murine gamma-herpesvirus 68, known as M11, binds to Beclin 1 with markedly high affinity in comparison with cellular Bcl-2 or Bcl-X(L) that interacts with Beclin 1 weakly.(1) Furthermore, the binding affinity directly correlated with the potency of inhibition of autophagosome formation in cells. Herein, we present additional data showing that Beclin 1 forms a large homo-oligomer, and this oligomerization is partly disrupted by the binding of M11. Oligomerized Beclin 1 is proposed to serve as a platform enabling a concerted action of many molecules of the associating proteins, including Bif-1 that could be directly involved in autophagosome biogenesis on membranes owing to its BAR domain.

MeSH terms

  • Animals
  • Apoptosis Regulatory Proteins / chemistry*
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / metabolism*
  • Beclin-1
  • Humans
  • Membrane Proteins / chemistry*
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Protein Conformation
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / metabolism*
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism

Substances

  • Apoptosis Regulatory Proteins
  • BECN1 protein, human
  • Beclin-1
  • Membrane Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Recombinant Fusion Proteins