Macroautophagy mediates the selective degradation of proteins and non-proteinaceous cellular constituents. Here, we show that the N-end rule pathway modulates macroautophagy. In this mechanism, the autophagic adapter p62/SQSTM1/Sequestosome-1 is an N-recognin that binds type-1 and type-2 N-terminal degrons (N-degrons), including arginine (Nt-Arg). Both types of N-degrons bind its ZZ domain. By employing three-dimensional modeling, we developed synthetic ligands to p62 ZZ domain. The binding of Nt-Arg and synthetic ligands to ZZ domain facilitates disulfide bond-linked aggregation of p62 and p62 interaction with LC3, leading to the delivery of p62 and its cargoes to the autophagosome. Upon binding to its ligand, p62 acts as a modulator of macroautophagy, inducing autophagosome biogenesis. Through these dual functions, cells can activate p62 and induce selective autophagy upon the accumulation of autophagic cargoes. We also propose that p62 mediates the crosstalk between the ubiquitin-proteasome system and autophagy through its binding Nt-Arg and other N-degrons.

Multiple myeloma (MM) is the second most common hematological malignancy and is characterized by the aberrant proliferation of terminally differentiated plasma B cells with impairment in apoptosis capacity. Particularly, osteolytic bone diseases and renal failure resulting from hyperparaproteinemia and hypercalcemia have been the major serious sequelae that are inextricably linked with MM tumor progression. Despite the introduction of new treatment regimens, problematic neuropathy, thrombocytopenia, drug resistance and high MM relapse rates continue to plague the current therapies. New chemical agents are in development on the basis of understanding several signaling pathways and molecular mechanisms like tumor necrosis factor-α, proteasome, PI3K and MARKs. This review focuses on the most recent patents and clinical trials in the development of new medicine for the treatment of multiple myeloma. Furthermore, the important signaling pathways involved in the proliferation, survival and apoptosis of myeloma cells will be discussed.