Portrait of the Month

Previous work in our lab has identified NBR1 (Neighbour of BRCA1) as a novel autophagy receptor that can bind both Atg8-like proteins as well as ubiquitinated substrates. NBR1 has a similar domain structure to another known autophagy receptor, p62/SQSTM1; i.e. both contain a N-terminal PB1, a central Zinc finger and C-terminal UBA domain. We have shown that NBR1 can bind Atg8-like proteins, both in vitro and in vivo, which is dependent on a C-terminal LC3 interacting region (LIR) and NBR1 accumulates in an autophagy and LIR dependent manner (Kirkin et al. Mol. Cell. 2009).
Elimination of damaged mitochondria, as well as clearance of mitochondria during differentiation is regulated by a specialized type of autophagy, i.e. mitophagy (Shweers et al. 2007; Kundu et al, 2008; Sandoval et al, 2008; Zhang et al, 2009). Previously, Nix/BNIP3L protein has been reported to be important for the process of mitochondrial clearance and terminal differentiation of reticulocytes (Zhang & Ney, 2009).

In addition to NBR1, we identified Nix/BNIP3L as an interaction partner for autophagy specific UBL proteins LC3/GABARAP and implicated in mitophagy (Novak et al. 2009). We show that Nix binds to LC3 and GABARAP through two potential LIRs. One of them is particularly important since mutation in W35 was able to abolish Nix:LC3/GABARAP binding in vitro and mitochondrial clearance in vivo.
Dysfunction of autophagy contributes or can be a cause of many diseases and failure of autophagy can promote cancer, neurodegenerative disorders, liver disease, premature aging, inflammatory diseases, such as Crohn´s, and compromises host defense against pathogens. The identification of novel autophagy receptors, such as NBR1 and Nix, will allow us to gain a deeper understanding of the overall process of autophagy and in particular, the mechanisms governing selective autophagy and how it may be deregulated in neurodegenerative, inflammatory diseases as well as cancer.