Different Roles of p62 (SQSTM1) Isoforms in Keratin-Related Protein Aggregation

Somlapura, Meghana; Gottschalk, Benjamin; Lahiri, Pooja; Kufferath, Iris; Pabst, Daniela; Rülicke, Thomas; Graier, Wolfgang F.; Denk, Helmut; Zatloukal, Kurt

doi:10.3390/ijms22126227

Cited by 8 publications

(11 citation statements)

References 48 publications

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“…Collectively, our findings document that p62 interacts with IκBα through a novel protein-interaction region which is independent of its many previously characterized structural protein-interacting regions including that with the innate defense regulator (IDR-1) peptide ( 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 60 ). This p62–IκBα interaction region, however, not only comprises its NLS1 ( 42 ) but is also precisely the region known to interact with the mutant Cu-Zn superoxide dismutase, SOD1, a mutant linked to amyotrophic lateral sclerosis ( 61 ).…”

Section: Discussionmentioning

confidence: 63%

“…To identify the p62 subdomains involved in its IκBα interaction, we carried out p62-deletion analyses through sequential deletion of various p62-plasmid regions corresponding to structural elements that interact with various cellular protein partners and/or motifs [Phox and Bem1p-domain (PB1), Zn-finger binding motifs (ZZ), TRAF6-binding (TB), LC3-interacting region, PEST1 and PEST2 motifs, Keap1-interacting region, and Ub-association region] ( 15 , 38 , 39 , 40 , 41 , 42 , 43 , 44 ) ( Fig. 2 ).…”

Section: Resultsmentioning

confidence: 99%

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In-Cell Chemical Crosslinking Identifies Hotspots for SQSTM-1/p62-IκBα Interaction That Underscore a Critical Role of p62 in Limiting NF-κB Activation Through IκBα Stabilization

Liu¹,

Trnka²,

Liang³

et al. 2023

Molecular & Cellular Proteomics

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Section: Discussionmentioning

confidence: 63%

Section: Resultsmentioning

confidence: 99%

In-Cell Chemical Crosslinking Identifies Hotspots for SQSTM-1/p62-IκBα Interaction That Underscore a Critical Role of p62 in Limiting NF-κB Activation Through IκBα Stabilization

Liu¹,

Trnka²,

Liang³

et al. 2023

Molecular & Cellular Proteomics

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“…Collectively, our findings document that p62 interacts with IκBα through a novel protein-interaction region which is independent of its many previously characterized structural protein-interacting regions including that with the innate defense regulator (IDR-1) peptide (34-40, 57). This p62-IκBα-interaction region, however not only comprises its NLS1 (38), but is also precisely the region known to interact with the mutant Cu-Zn superoxide dismutase, SOD1, a mutant linked to amyotrophic lateral sclerosis (ALS) (58).…”

Section: Discussionmentioning

confidence: 65%

In-cell chemical crosslinking identifies hotspots for p62-IκBα interaction that underscore a critical role of p62 in limiting NF-κB activation through IκBα-stabilization

Liu

Trnka

Liang

et al. 2022

Preprint

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We have previously documented that in liver cells, the multifunctional protein scaffold p62/SQSTM1 is closely associated with IκBα, an inhibitor of the transcriptional activator NF-κB. Such an intimate p62-IκBαassociation we now document leads to a marked 18-fold proteolytic IκBα-stabilization, enabling its nuclear entry and termination of the NF-κB-activation cycle. In p62-/--cells, such termination is abrogated resulting in the nuclear persistence and prolonged activation of NF-κB following inflammatory stimuli. Utilizing various approaches both classic (structural deletion, site-directed mutagenesis) as well as novel (in cell chemical crosslinking), coupled with proteomic analyses, we have defined the precise structural hotspots of p62-IκBα association. Accordingly, we have identified such IκBα hotspots to reside around N-terminal (K38, K47 and K67) and C-terminal (K238/C239) residues in its 5th ankyrin repeat domain. These sites interact with two hotspots in p62: One in its PB-1 subdomain around K13, and the other comprised of a positively charged patch (R183/R186/K187/K189) in the intervening region between its ZZ- and TB-subdomains. APEX proximity analyses upon IκBα co-transfection of cells with and without p62 have enabled the characterization of the p62 influence on IκBα-protein-protein interactions. Interestingly, consistent with p62 capacity to proteolytically stabilize IκBα, its presence greatly impaired IκBα interactions with various 20S/26S proteasomal subunits. Furthermore, consistent with p62-interaction with IκBα on an interface opposite to that of its NF-κB-interacting interface, p62 failed to significantly affect IκBα-NF-κB interactions. These collective findings together with the known dynamic p62 nucleocytoplasmic shuttling, leads us to speculate that it may be involved in piggy-back nuclear transport of IκBα following its NF-κB-elicited transcriptional activation and de novo synthesis, required for the termination of the NF-κB-activation cycle. Consequently, mice carrying a liver specific deletion of p62-residues 68-252 harboring its positively charged patch, reveal age-dependent enhanced liver inflammation. Our findings reveal yet another mode of p62-mediated pathophysiologically relevant regulation of NF-κB.

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“…As aforementioned, an ATG16L1 variant (T600A) stimulates an anti-tumor immune response and is associated with a good prognosis (99). SQSTM1 is expressed in several variants: N-Ter truncated isoform lacking the domain responsible for SQSTM1 oligomerization and autophagic cargo sorting ability (146); splice variant affecting the p62/Keap1/NRF2 axis (147) and SQSTM1 3' untranslated region-truncated variant associated with aggressiveness and resistance to therapy in patients with breast cancer (148). Therefore, it would be of interest to determine whether these different AMMs isoforms exhibit autophagy-independent functions.…”

Section: Discussionmentioning

confidence: 99%

Beyond self‑eating: Emerging autophagy‑independent functions for the autophagy molecules in cancer (Review)

Tedesco,

Santarosa,

Maestro

2024

Int J Oncol

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Autophagy is a conserved catabolic process that controls organelle quality, removes misfolded or abnormally aggregated proteins and is part of the defense mechanisms against intracellular pathogens. Autophagy contributes to the suppression of tumor initiation by promoting genome stability, cellular integrity, redox balance and proteostasis. On the other hand, once a tumor is established, autophagy can support cancer cell survival and promote epithelial-to-mesenchymal transition. A growing number of molecules involved in autophagy have been identified. In addition to their key canonical activity, several of these molecules, such as ATG5, ATG12 and Beclin-1, also exert autophagy-independent functions in a variety of biological processes. The present review aimed to summarize autophagy-independent functions of molecules of the autophagy machinery and how the activity of these molecules can influence signaling pathways that are deregulated in cancer progression. Contents 1. Introduction 2. Autophagic cascade 3. Autophagy-independent role of AMMs and cancer 4. Non-autophagic functions of AMMs in genome stability and cell proliferation 5. Unconventional role of AMMs in cell death and survival 6. AMMs acting beyond autophagy in metastasis and immune microenvironment 7. microRNAs (miRNAs or miRs) in the control of AMMs 8. Diagnostic and prognostic role of AMMs in cancer 9. Conclusions and perspectives

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Different Roles of p62 (SQSTM1) Isoforms in Keratin-Related Protein Aggregation

Cited by 8 publications

References 48 publications

In-Cell Chemical Crosslinking Identifies Hotspots for SQSTM-1/p62-IκBα Interaction That Underscore a Critical Role of p62 in Limiting NF-κB Activation Through IκBα Stabilization

In-Cell Chemical Crosslinking Identifies Hotspots for SQSTM-1/p62-IκBα Interaction That Underscore a Critical Role of p62 in Limiting NF-κB Activation Through IκBα Stabilization

In-cell chemical crosslinking identifies hotspots for p62-IκBα interaction that underscore a critical role of p62 in limiting NF-κB activation through IκBα-stabilization

Beyond self‑eating: Emerging autophagy‑independent functions for the autophagy molecules in cancer (Review)

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