p62 (SQSTM1) forms part of a novel, reversible aggregate containing a specific conformer of the cAMP degrading phosphodiesterase, PDE4A4.

Cells employ macroautophagy to deliver aggregates of misfolded and/or ubiquitinated proteins for lysosomal degradation or supply of essential macromolecules under conditions of nutrient deprivation. The former seems complementary to the proteasome system, which is likely to degrade only soluble proteins. While bulk degradation via the autophagy pathway during starvation is rather nonspecific, the recognition of proteins that are either misfolded or adopt a particular conformation and/or become ubiquitinated, requires some form of specificity. This is brought about, at least in part, by the scaffold and ubiquitin-binding protein, p62 (SQSTM1). p62 is a multidomain scaffold that sequesters other proteins and polymerizes through its Phox and Bem1p domains and binds K63-ubiquitinated proteins through its UBA domain. p62 interaction with LC3 appears critical for membrane encapsulation seen in autophagosomes. However, there is a growing body of evidence indicating that p62 is not exclusively involved in autophagy regulation, and that there are nonmembrane encapsulated, soluble subpopulations of p62 in cells. The role of these subpopulations has yet to be resolved, although one function appears to be to regulate signaling, as indicated through p62's ability to regulate NFκB activation. Signaling through the ubiquitous cyclic AMP (cAMP) system is compartmentalized, with tethered subpopulations of cAMP-degrading phosphodiesterases sculpting cAMP gradients around specific signaling complexes so as to regulate them at a spatial level. We have recently demonstrated that p62 colocalizes with a specific conformer of the cAMP degrading phosphodiesterase, PDE4A4, so as to form reversible, membrane-free cytosolic aggregates lacking LC3. This results in PDE4A4 becoming sequestered away from signaling proteins that normally sequester it, providing a means of reprogramming compartmentalized cAMP signaling in cells.