Basic Research Paper

Autophagy inhibition promotes defective neosynthesized proteins storage in ALIS, and induces redirection toward proteasome processing and MHCI-restricted presentation

Volume 8, Issue 3   March 2012
Pages 350 - 363
http://dx.doi.org/10.4161/auto.18806
Keywords: Atg5, DRiPs, NBR1, SQSTM1, antigen presentation
Authors: Till Wenger, Seigo Terawaki, Voahirana Camosseto, Ronza Abdelrassoul, Anna Mies, Nadia Catalan, Nuno Claudio, Giovanna Clavarino, Aude de Gassart, Francesca de Angelis Rigotti, Evelina Gatti and Philippe Pierre

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Abstract:
A significant portion of newly synthesized protein fails to fold properly and is quickly degraded. These defective ribosomal products (DRiPs) are substrates for the ubiquitin-proteasome system (UPS) and give rise to a large fraction of peptides presented by major histocompatibility complex class I molecules (MHCI). Here, we showed that DRiPs are also autophagy substrates, which accumulate upon autophagy inhibition in aggresome-like-induced structures (ALIS). Aggregation is critically depending on p62/SQSTM1, but occurs in the absence of activation of the NRF2 signaling axis and transcriptional regulation of p62/SQSTM1. We demonstrated that autophagy-targeted DRiPs can become UPS substrates and give rise to MHCI presented peptides upon autophagy inhibition. We further demonstrated that autophagy targeting of DRiPs is controlled by NBR1, but not p62/SQSTM1, CHIP or BAG-1. Active autophagy therefore directly modulates MHCI presentation by constantly degrading endogenous defective neosynthesized antigens, which are submitted to at least two distinct quality control mechanisms.

Received: September 9, 2011; Accepted: November 18, 2011; Published Online: March 1, 2012

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