Cytoplasmic DAXX drives SQSTM1/p62 phase condensation to activate Nrf2-mediated stress response

Abstract

Autophagy cargo recognition and clearance are essential for intracellular protein quality control. SQSTM1/p62 sequesters intracellular aberrant proteins and mediates cargo delivery for their selective autophagic degradation. The formation of p62 non-membrane-bound liquid compartments is critical for its function as a cargo receptor. The regulation of p62 phase separation/condensation has yet been poorly characterised. Using an unbiased yeast two-hybrid screening and complementary approaches, we found that DAXX physically interacts with p62. Cytoplasmic DAXX promotes p62 puncta formation. We further elucidate that DAXX drives p62 liquid phase condensation by inducing p62 oligomerisation. This effect promotes p62 recruitment of Keap1 and subsequent Nrf2-mediated stress response. The present study suggests a mechanism of p62 phase condensation by a protein interaction, and indicates that DAXX regulates redox homoeostasis, providing a mechanistic insight into the prosurvival function of DAXX.

The Overlapping Genetics of Amyotrophic Lateral Sclerosis and Frontotemporal Dementia

“…Similar to TDP-43 and FUS, SQSTM1 goes through liquid-liquid phase separation. Recent research shows that cytoplasmic DAXX drives SQSTM1/p62 phase condensation, an essential step in the activation of Nrf2-mediated stress response (Yang et al, 2019). Polyubiquitin chain-induced p62 phase separation leads to the segregation of autophagic cargo (Herhaus and Dikic, 2018;Sun et al, 2018).…”

p62: Friend or Foe? Evidences for OncoJanus and NeuroJanus Roles

“…Phase condensation of p62 in non-membrane liquid compartment is crucial for its role of cargo receptor. In this regard, evidence has been provided that p62 “puncta formation”, the process of liquid–liquid phase separation that is needed for p62 oligomerization is enhanced by the cytoplasmic histone H3F3/H3.3 chaperone DAXX [ 33 ].…”

Protein phase separation: A novel therapy for cancer?

“…Modulates cancer cell growth Induces autophagy (Sen, Gispert, & Auburger, 2017;Yang, Willis, et al, 2019) Abbreviations: ATG, autophagy-related; BRD4, bromodomain containing 4; CAPRIN1, cell cycle-associated protein 1; CBX2, chromobox 2; cGAS, cyclic GMP-AMP synthase; eRNP, enhancer RNA-dependent ribonucleoprotein; FMRP, fragile X mental retardation protein; HP1α, heterochromatin protein 1α; HSF1, heat shock transcription factor 1; MED1, mediator complex subunit 1; m 6 A, N 6-methyladenosine; NPC, nuclear pore complex; NPM1, nucleophosmin 1; P-TEFb, positive transcription elongation factor b; PBP1, Poly(A) binding protein-binding protein 1; RBM14, RNA binding motif protein 14; SOS, son of sevenless; SPOP, speckle-type BTB/POZ protein; TCR, T cell receptor; TPX2, targeting protein for xenopus kinesin-like protein 2; TP53BP1, tumor protein p53-binding protein 1; UBQLN2, ubiquilins-2; ZO, zona occludens. S979R; S990N; S1000F; S1021Hfs*51; S1042L; S1042=; S1049C; S1091F; S1109F; S1111L; S1116N; S1124R; S1128=; S1129G; S1137F; S1143C; S1149F; S1156F Abbreviations: CAPRIN1, cell cycle-associated protein 1; CBX2, chromobox 2; cGAS, cyclic GMP-AMP synthase; FMRP, fragile X mental retardation protein; HP1α, heterochromatin protein 1α; HSF1, heat shock transcription factor 1; MED1, mediator complex subunit 1; NPM1, nucleophosmin 1; PBP1, Poly(A) binding protein-binding protein 1; SOS, son of sevenless; SPOP, speckle-type BTB/POZ protein; TPX2, targeting protein for xenopus kinesin-like protein 2; TP53BP1, tumor protein p53-binding protein 1; UBQLN2, ubiquilins-2 phase-separated condensates at the sites of super-enhancers-driven transcription (Sabari et al, 2018), which can concentrate and compartmentalize the transcription apparatuses at super-enhancersregulated genes and recruit super-enhancers components to activate transcription.…”

“…In addition to containing the low-complexity domains, the concentration of the proteins involved in phase separation is extremely important to drive phase separation (Alberti & Dormann, 2019). The condensates formed by phase-separated proteins are essentially collections of molecules with a high concentration in a certain space, indicating that the alteration of concentration will influence the formation and scale of phase separation, thus affecting their normal function (Sabari et al, 2018;Yang, Willis, et al, 2019).…”