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. 2013 Oct;15(10):1220-30.
doi: 10.1038/ncb2847. Epub 2013 Sep 22.

The deubiquitylase USP33 discriminates between RALB functions in autophagy and innate immune response

Michal Simicek  1 , Sam Lievens, Mathias Laga, Dmytro Guzenko, Vasily N Aushev, Peter Kalev, Maria Francesca Baietti, Sergei V Strelkov, Kris Gevaert, Jan Tavernier, Anna A Sablina
Affiliations

The deubiquitylase USP33 discriminates between RALB functions in autophagy and innate immune response

Michal Simicek et al. Nat Cell Biol. 2013 Oct.

Abstract

The RAS-like GTPase RALB mediates cellular responses to nutrient availability or viral infection by respectively engaging two components of the exocyst complex, EXO84 and SEC5. RALB employs SEC5 to trigger innate immunity signalling, whereas RALB-EXO84 interaction induces autophagocytosis. How this differential interaction is achieved molecularly by the RAL GTPase remains unknown. We found that whereas GTP binding turns on RALB activity, ubiquitylation of RALB at Lys 47 tunes its activity towards a particular effector. Specifically, ubiquitylation at Lys 47 sterically inhibits RALB binding to EXO84, while facilitating its interaction with SEC5. Double-stranded RNA promotes RALB ubiquitylation and SEC5-TBK1 complex formation. In contrast, nutrient starvation induces RALB deubiquitylation by accumulation and relocalization of the deubiquitylase USP33 to RALB-positive vesicles. Deubiquitylated RALB promotes the assembly of the RALB-EXO84-beclin-1 complexes driving autophagosome formation. Thus, ubiquitylation within the effector-binding domain provides the switch for the dual functions of RALB in autophagy and innate immune responses.

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