PB1 and UBA domains of p62 are essential for aggresome-like induced structure formation

Cabe, Maleen; Rademacher, David J.; Karlsson, Amelia; Cherukuri, Srinivas; Bakowska, Joanna C.

doi:10.1016/j.bbrc.2018.06.153

Cited by 31 publications

(29 citation statements)

References 23 publications

(54 reference statements)

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“…Specifically, we observed that Tau RD-YFP aggregates, or factors belonging to the same insoluble complexes, were ubiquitinylated and colocalized with the autophagy adapter p62. Consistently, they were specifically labeled by Lys 63 type of ubiquitin chains, in accordance with their recognition as autophagy cargo by p62 (Cabe et al, 2018;Zaffagnini et al, 2018). However, both proteasomal degradation and autophagy (Lee et al, 2013) failed to clear endogenous filaments in our neuronal cell model.…”

Section: Fate Of Tau Fibrils In Neuronal Cellssupporting

confidence: 80%

Fate and propagation of endogenously formed Tau aggregates in neuronal cells

et al. 2020

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Tau accumulation in the form of neurofibrillary tangles in the brain is a hallmark of tauopathies such as Alzheimer's disease (AD). Tau aggregates accumulate in brain regions in a defined spatiotemporal pattern and may induce the aggregation of native Tau in a prion-like manner. However, the underlying mechanisms of cell-to-cell spreading of Tau pathology are unknown and could involve encapsulation within exosomes, trans-synaptic passage, and tunneling nanotubes (TNTs). We have established a neuronal cell model to monitor both internalization of externally added fibrils, synthetic (K18) or Tau from AD brain extracts, and real-time conversion of microtubule-binding domain of Tau fused to a fluorescent marker into aggregates. We found that these endogenously formed deposits colabel with ubiquitin and p62 but are not recruited to macroautophagosomes, eventually escaping clearance. Furthermore, endogenous K18-seeded Tau aggregates spread to neighboring cells where they seed new deposits. Transfer of Tau aggregates depends on direct cell contact, and they are found inside TNTs connecting neuronal cells. We further demonstrate that contact-dependent transfer occurs in primary neurons and between neurons and astrocytes in organotypic cultures.

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Section: Fate Of Tau Fibrils In Neuronal Cellssupporting

confidence: 80%

Fate and propagation of endogenously formed Tau aggregates in neuronal cells

et al. 2020

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“…SQSTM1 (also called p62) is a scaffold ubiquitin-binding protein that targets proteins for degradation by selective autophagy [138,139,140,141,142,143]. It is a 440 amino acid protein (Figure 2) with a N-terminal self-oligomerization domain (the PB1 domain) followed by a central zinc finger (ZZ) and a tumor necrosis factor receptor-associated factor 6 (TRAF6)-binding domain (TB) [144].…”

Section: Sqstm1-nup214: Playing With Autophagymentioning

confidence: 99%

“…ALIS are transient cytoplasmic aggregates that are generated in response to cellular stress. They serve as storage sites for polyubiquitinated proteins destined for proteasomal degradation [140,143]. The formation of ALIS is in fact dependent on SQSTM1.…”

Section: Sqstm1-nup214: Playing With Autophagymentioning

confidence: 99%

NUP214 in Leukemia: It’s More than Transport

Mendes

Fahrenkrog

2019

Cells

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NUP214 is a component of the nuclear pore complex (NPC) with a key role in protein and mRNA nuclear export. Chromosomal translocations involving the NUP214 locus are recurrent in acute leukemia and frequently fuse the C-terminal region of NUP214 with SET and DEK, two chromatin remodeling proteins with roles in transcription regulation. SET-NUP214 and DEK-NUP214 fusion proteins disrupt protein nuclear export by inhibition of the nuclear export receptor CRM1, which results in the aberrant accumulation of CRM1 protein cargoes in the nucleus. SET-NUP214 is primarily associated with acute lymphoblastic leukemia (ALL), whereas DEK-NUP214 exclusively results in acute myeloid leukemia (AML), indicating different leukemogenic driver mechanisms. Secondary mutations in leukemic blasts may contribute to the different leukemia outcomes. Additional layers of complexity arise from the respective functions of SET and DEK in transcription regulation and chromatin remodeling, which may drive malignant hematopoietic transformation more towards ALL or AML. Another, less frequent fusion protein involving the C terminus of NUP214 results in the sequestosome-1 (SQSTM1)-NUP214 chimera, which was detected in ALL. SQSTM1 is a ubiquitin-binding protein required for proper autophagy induction, linking the NUP214 fusion protein to yet another cellular mechanism. The scope of this review is to summarize the general features of NUP214-related leukemia and discuss how distinct chromosomal translocation partners can influence the cellular effects of NUP214 fusion proteins in leukemia.

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“…However, whether this polyubiquitination is K48-linked or K63-linked is still unclear. In addition, the UBA (ubiquitin associated) domain of p62 can bind to both K48- and K63-linked (with a higher affinity) polyubiquitin chains and regulate autophagic protein turnover [53]. These led us to further investigate the nature of polyubiquitinated chains associated with EBNA3C in the absence or presence of MG132.…”

Section: Resultsmentioning

confidence: 99%

Proteasomal Inhibition Triggers Viral Oncoprotein Degradation via Autophagy-Lysosomal Pathway

Gain¹,

Malik²,

Bhattacharjee³

et al. 2019

Preprint

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26 Epstein-Barr virus (EBV) nuclear oncoprotein EBNA3C is essential for B-cell transformation 27 and development of several B-cell lymphomas particularly those are generated in an immuno-28 compromised background. EBNA3C recruits ubiquitin-proteasome machinery for deregulating 29 multiple cellular oncoproteins and tumor suppressor proteins. Although EBNA3C is found to be 30 ubiquitinated at its N-terminal region and interacts with 20S proteasome, the viral protein is 31 surprisingly stable in growing B-lymphocytes. EBNA3C can also circumvent autophagy-lysosomal 32 mediated protein degradation and subsequent antigen presentation for T-cell recognition. Recently, 33 we have shown that EBNA3C enhances autophagy, which serve as a prerequisite for B-cell survival 34 particularly under growth deprivation conditions. We now demonstrate that proteasomal inhibition 35 by MG132 induces EBNA3C degradation both in EBV transformed B-lymphocytes and ectopic-36 expression systems. Interestingly, MG132 treatment promotes degradation of two EBNA3 family 37 oncoproteins -EBNA3A and EBNA3C, but not the viral tumor suppressor protein EBNA3B. EBNA3C 38 degradation induced by proteasomal inhibition is partially blocked when autophagy-lysosomal 39 pathway is inhibited. In response to proteasomal inhibition, EBNA3C is predominantly K63-linked 40 polyubiquitinated, colocalized with the autophagy-lsyosomal fraction in the cytoplasm and 41 participated within p62-LC3B complex, which facilitates autophagy-mediated degradation. We 42 further show that the degradation signal is present at the first 50 residues of the N-terminal region 43 of EBNA3C. Proteasomal inhibition reduces the colony formation ability of this important viral 44 oncoprotein, increases transcriptional activation of both latent and lytic gene expression and 45 induces viral reactivation from EBV transformed B-lymphocytes. Altogether, this study offers 46 rationale to use proteasome inhibitors as potential therapeutic strategy against multiple EBV 47 associated B-cell lymphomas, where EBNA3C is expressed. 48 49 50 3 | P a g e 51 Author Summary 52 Epstein-Barr virus (EBV) establishes latent infection in B-lymphocytes and is associated with 53 a number of human malignancies, both of epithelial and lymphoid origin. EBV encoded EBNA3 54 family of nuclear latent antigens comprising of EBNA3A, EBNA3B, and EBNA3C are unique to 55 immunoblastic lymphomas. While EBNA3A and EBNA3C are involved in blocking many important 56 tumor suppressive mechanisms, EBNA3B exhibits tumor suppressive functions. Although EBNA3 57 proteins, in particular EBNA3C, interact with and employ different protein degradation machineries 58 to induce B-cell lymphomagenesis, these viral proteins are extremely stable in growing B-59 lymphocytes. To this end, we now demonstrate that proteasomal inhibition leads to specifically 60 degradation of oncogenic EBNA3A and EBNA3C proteins, whereas EBNA3B remains unaffected. 61 Upon proteasomal inhibition, EBNA3C degradation occurs via autophagy-lysosomal pathway, 62 thro...

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PB1 and UBA domains of p62 are essential for aggresome-like induced structure formation

Cited by 31 publications

References 23 publications

Fate and propagation of endogenously formed Tau aggregates in neuronal cells

Fate and propagation of endogenously formed Tau aggregates in neuronal cells

NUP214 in Leukemia: It’s More than Transport

Proteasomal Inhibition Triggers Viral Oncoprotein Degradation via Autophagy-Lysosomal Pathway

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