DEFINITION
It is a multifunctional protein with 440 amino acids, with a molecular weight of 62 kDa and it presents two isoforms.
Protein Aminoacids Percentage
CHEMICAL STRUCTURE
It presents 9 protein-interacting domains. At the end terminal there is the SH2 domain of p56lck. The acidic interaction domain (AID) interacts with atypical protein kinase Cs (aPKCs). These two domains are often taken together and named PB1. The zinc finger motif (ZZ) domain of SQSTM1 is needed for the interaction with the scaffold protein RIP (receptor interaction protein) that recruits aPKCs to tumor necrosis factor-α (TNFα)-signaling complexes. The next domain has been identified to bind to p38, resulting in p38 MAPK (mitogen-activated protein kinase) activation, as well as to proteins containing the LIM (Lin11, Isl-1, and Mec-3) domain, followed by the TNF receptor-associated factor 6 (TRAF6)-binding domain. Between the 2 domains that are rich of the amino acids proline (P), glutamic acid (E), serine (S), and threonine (T) (forming the PEST domain), there is an LC3-interacting region that binds autophagic effector proteins, inducing SQSTM1 degradation by autophagy. At the C-terminus of SQSTM1 is the UBA domain.
http://www.uniprot.org/uniprot/Q13501
FUNCTION
The most important functions of p62 are its role in NF-kB pathway and in autophagy.
ROLE OF SQSTM1 IN NF-kB PATHWAY
The most crucial function of SQSTM1 is its scaffolding characteristics in the RANKL-induced NFκB signaling. When RANKL binds to its receptor RANK on the osteoclasts, the cytoplasmic domain of RANK recruits ubiquilated TRAF6 that attracts SQSTM1. Then, SQSTM1 recruits aPKCs that phosphorylate and activate inhibitor of κB kinase β (IKKβ) of an IKK complex, composed of IKKα, IKKβ, and NEMO (NFκB essential modulator or IKKγ). Subsequently, the inhibitor of κB (IκB) is phosphorylated and targeted K48-linked ubiquitinously for proteasomal protein degradation, followed by discharging NFκB that is assembled with the p50 and p65 subunits. NFκB migrates to the nucleus and activates the target genes of osteoclastogenesis for transcription. An alternative manner to activate NFκB is initiated by K63-linked ubiquitination of TRAF6 by intrinsic E3 ligase activity (autoubiquitination) or regulated by SQSTM1, followed by forming a complex with TAB2 (TAK1 binding protein) and TAK1 (tumor growth factor-β activated kinase 1). The activation of TAK1 through phosphorylation by TAB2 induces K63-linked ubiquitination on NEMO. On its turn, NEMO phosphorylates IKKα/β, followed by the NFκB sequels.
Insights into the pathogenesis of Paget's disease 2010
AUTOPHAGY
Thanks to its interaction with LC3 (light chain 3), an autophagosome marker, it seems that p62 forms aggregates with the ubiquitinated proteins that have to be degraded facilitating their cleareance. Impairments in this mechanism lead to accumulation of p62-containing aggregates seen in patients with Alzheimer disease, Parkinson’s disease, Pick’s disease, dementia with Lewy bodies, PDB (can fit the late onset of the disease) and FEO.
sequestosome1/p62 across diseases 2012
p62/SQSTM1 autophagy 2005
APOPTOSIS
A recent study suggests that p62 could play a role in the extrinsic pathway of apoptosis. On binding of extracellular triggers such as TRAIL (TNF-related apoptosis-inducing ligand) or TRAIL-receptor 1 (TRAIL-R1) and/or 2 (TRAIL-R2), the receptors recruit Fas-associated death domain adaptor proteins through the death domain of the adaptor proteins. These proteins, in turn, recruit caspases 8 via their death effector domain, forming a death-inducing signaling complex. Then, ubiquitination of caspases 8 by cullin 3 follows. The ubiquitinated caspases 8 are subsequently translocated from the receptor complex into the cytosol by SQSTM1, continuing the apoptotic cascade.
Luca Savoldi,
Emanuele Coda
