The higher-order molecular organization of p62/SQSTM1

The multifunctional signaling adaptor and selective autophagy receptor p62/SQSTM1 is commonly found in dense light-microscopic loci of eukaryotic cells. Recently, Ciuffa et al. demonstrated that p62 is able to form organized polymers of helical symmetry once purified and reconstituted in the test tube [1]. In selective autophagy, p62 acts both as a substrate and as a receptor to bridge LC3 attached to the autophagosomal membrane with ubiquitinated cargo destined for degradation in the lysosome [2]. In signaling, p62 acts as an adaptor protein by interacting with protein kinases (atypical protein kinase C, MEKK3, MEK5, ERK1 and RIP) and ubiquitin ligases such as TRAF6 and the KEAP1-Cul3 complex [3]. Hence, p62 is acting in important signaling pathways involving NFκB, NRF2 (NFE2L2), mTOR, Wnt and others. Evidence is accumulating that the signaling and autophagy roles of p62 come together in the regulation of inflammation, innate immunity, oxidative stress, cell death and tumorigenesis. p62 is located in polyubiquitincontaining protein aggregates in cultured cells and in brain tissues in neurodegenerative diseases and in liver cancers. In these situations the degradative autophagy machinery is overwhelmed and unable to cope with removal of excessive protein deposits [2, 4]. Oligomerization of p62 via the PB1 domain is required for formation of p62 bodies in cells and degradation by selective autophagy, and for signaling via the NRF2-mediated oxidative stress response pathway [2]. Structural studies on the protein had been hampered by the fact p62 formed aggregates mediated via the N-terminal PB1 domain. Thus, X-ray crystallographic and NMR structural information on the protein had only been obtained from isolated PB1 domains by preventing it to form large assemblies. While the central part of the protein containing the LC3 interacting region (LIR) is predicted to be disordered, the C-terminal part is composed of the folded UBA domain that recognizes ubiquitinated cargo and had only been structurally characterized in isolation. The recent structural analysis of Ciuffa et al. from a series of successively longer parts of p62 by electron cryomicroscopy (cryo-EM) revealed that the PB1 domain alone is sufficient to form helical polymers with significant flexibility and curvature (Figure 1) [1]. The cryo-EM maps resolved at 10.3 and 10.9 Å reveal a common Editorial