IPO3-mediated Nonclassical Nuclear Import of NF-κB Essential Modulator (NEMO) Drives DNA Damage-dependent NF-κB Activation

Hwang, Byounghoon; McCool, Kevin W.; Wan, Jun; Wuerzberger-Davis, Shelly M.; Young, Elton T.; Choi, Eun Young; Cingolani, Gino; Weaver, Beth A.; Miyamoto, Shigeki

doi:10.1074/jbc.m115.645960

Cited by 17 publications

(20 citation statements)

References 79 publications

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“…3I and J), which provided further evidence that TRIM37 mediated monoubiqutination of NEMO in the nucleus. Remarkably, the etoposide-induced association of NEMO with Ran, an export receptor and the cargo protein for nuclear export of NEMO (29), was increased in TRIM37-transduced cells but was nearly undetectable in TRIM37 À/À cells, and no interaction of Ran and NEMO/K309A was observed (Fig. 3K).…”

Section: Trim37 Promotes Nuclear Export Of Nemomentioning

confidence: 94%

An ATM/TRIM37/NEMO Axis Counteracts Genotoxicity by Activating Nuclear-to-Cytoplasmic NF-κB Signaling

Song

Zhu

et al. 2018

Cancer Research

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Blocking genotoxic stress-induced NF-kB activation would substantially enhance the anticancer efficiency of genotoxic chemotherapy. Unlike the well-established classical NF-kB pathway, the genotoxic agents-induced "nuclear-tocytoplasmic" NF-kB pathway is initiated from the nucleus and transferred to the cytoplasm. However, the mechanism linking nuclear DNA damage signaling to cytoplasmic IKK activation remains unclear. Here, we report that TRIM37, a novel E3 ligase, plays a vital role in genotoxic activation of NF-kB via monoubiquitination of NEMO at K309 in the nucleus, consequently resulting in nuclear export of NEMO and IKK/NF-kB activation. Clinically, TRIM37 levels correlated positively with levels of activated NF-kB and expression of Bcl-xl and XIAP in esophageal cancer specimens, which also associated positively with clinical stage and tumor-nodemetastasis classification and associated inversely with overall and relapse-free survival in patients with esophageal cancer. Overexpression of TRIM37 conferred resistance to the DNA-damaging anticancer drug cisplatin in vitro and in vivo through activation of the NF-kB pathway. Genotoxic stress-activated ATM kinase directly interacted with and phosphorylated TRIM37 in the cytoplasm, which induced translocation of TRIM37 into the nucleus, where it formed a complex with NEMO and TRAF6 via a TRAF6-binding motif (TBM). Importantly, blocking the ATM/TRIM37/NEMO axis via cell-penetrating TAT-TBM peptide abrogated genotoxic agent-induced NEMO monoubiquitination and NF-kB activity, resulting in hypersensitivity of cancer cells to genotoxic drugs. Collectively, our results unveil a pivotal role for TRIM37 in genotoxic stress and shed light on mechanisms of inducible chemotherapy resistance in cancer. Significance: In response to genotoxic stress, TRIM37 activates NF-kB signaling via monoubiquitination of NEMO, which subsequently promotes cisplatin chemoresistance and tumor relapse in cancer. Cancer Res; 78(22); 6399-412. Ó2018 AACR.

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Section: Trim37 Promotes Nuclear Export Of Nemomentioning

confidence: 94%

An ATM/TRIM37/NEMO Axis Counteracts Genotoxicity by Activating Nuclear-to-Cytoplasmic NF-κB Signaling

Song

Zhu

et al. 2018

Cancer Research

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“…GST-JAK1 NLS fragments were generated by amplifying the fragment spanning nucleotide 982 to 1119 by PCR using either wild type JAK1 or cNLS mutated JAK1 as template, and then subcloning into BamHI and EcoRI restriction sites of pGEX6p-1 vector. Flag-KPNA constructs were previously described (25). HA-KPNAs were generated by amplifying KPNA with PCR (forward primer contains HA tag sequence) and subcloning into BamHI and XhoI restriction sites of pRetroCMV_TO_Hygro vector (eGFP negative).…”

Section: Methodsmentioning

confidence: 99%

“…Classical nuclear import of these large proteins depends on a nuclear localization signal (NLS), generally a short stretch of basic amino acids (either alone or separated by a linker region of 10–12 amino acids), which is directly recognized by one or more of seven importin α subunits (KPNA1-7) (23–25). After recognition of its cargos, importin α binds to importin β1 (KPNB1) to form the cargo-importin α –importin β1 complex, which is then transported into the nucleus through the nuclear pore complex.…”

Section: Introductionmentioning

confidence: 99%

Nuclear Import of JAK1 Is Mediated by a Classical NLS and Is Required for Survival of Diffuse Large B-cell Lymphoma

Zhu

Hwang

Miyamoto

et al. 2017

Molecular Cancer Research

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Janus kinases (JAKs) are non-receptor tyrosine kinases that are generally found in association with cytokine receptors. In the canonical pathway, roles of JAKs have well been established in activating signal transducers and activators of transcription (STATs) in response to cytokine stimulation to modulate gene transcription. In contrast, a non-canonical role of JAK2 has recently been discovered in which JAK2 in the nucleus imparts the epigenetic regulation of gene transcription through phosphorylation of tyrosine 41 on the histone protein H3. Recent work further demonstrated that this non-canonical mechanism is conserved with JAK1, which is activated by the autocrine cytokines IL-6 and IL-10 in activated B-cell-like diffuse large B cell lymphoma (ABC DLBCL), a cancer type that is particularly difficult to treat and has poor prognosis. However, how JAK1 gains access to the nucleus to enable epigenetic regulation remains undefined. Here we investigated this question and revealed that JAK1 has a classical nuclear localization signal (cNLS) toward the N-terminal region, which can be recognized by multiple importin alpha isoforms. Moreover, the nuclear import of JAK1 is independent of its kinase activity but is required for the optimal expansion of ABC DLBCL cells in vitro. Implications: This study demonstrates that the nuclear import of JAK1 is essential for the optimal fitness of ABC DLBCL cells and targeting JAK1 nuclear localization is a potential therapeutic strategy for ABC DLBCL.

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“…The mechanism underlying this first step of its translocation is not clear, since NEMO lacks a classical nuclear localization signal that would be recognized by importins [32,33]. However, a recent report by Hwang and colleagues demonstrated that NEMO interacts with the importin β family member IPO3 and translocates to the nucleus [34]. At present, we can only speculate but favour a model in which the Ku70/ NEMO interaction modulates NEMO translocation to the nucleus.…”

Section: Discussionmentioning

confidence: 84%

DNA-PK: gatekeeper for IKKγ/NEMO nucleocytoplasmic shuttling in genotoxic stress-induced NF-kappaB activation

Medunjanin

Putzier

Nöthen

et al. 2020

Cell. Mol. Life Sci.

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The transcription factors of the nuclear factor κB (NF-κB) family play a pivotal role in the cellular response to DNA damage. Genotoxic stress-induced activation of NF-κB differs from the classical canonical pathway by shuttling of the NF-κB Essential Modifier (IKKγ/NEMO) subunit through the nucleus. Here, we show that DNA-dependent protein kinase (DNA-PK), an enzyme involved in DNA double-strand break (DSB) repair, triggers the phosphorylation of NEMO by genotoxic stress, thereby enabling shuttling of NEMO through the nucleus with subsequent NF-κB activation. We identified serine 43 of NEMO as a DNA-PK phosphorylation site and point mutation of this serine to alanine led to a complete block of NF-κB activation by ionizing radiation (IR). Blockade of DNA-PK by a specific shRNA or by DNA-PKcs-deficient cells abrogated NEMO entry into the nucleus, as well. Accordingly, SUMOylation of NEMO, a prerequisite of nuclear NEMO, was abolished. Based on these observations, we propose a model in which NEMO phosphorylation by DNA-PK provides the first step in the nucleocytoplasmic trafficking of NEMO.

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IPO3-mediated Nonclassical Nuclear Import of NF-κB Essential Modulator (NEMO) Drives DNA Damage-dependent NF-κB Activation

Cited by 17 publications

References 79 publications

An ATM/TRIM37/NEMO Axis Counteracts Genotoxicity by Activating Nuclear-to-Cytoplasmic NF-κB Signaling

An ATM/TRIM37/NEMO Axis Counteracts Genotoxicity by Activating Nuclear-to-Cytoplasmic NF-κB Signaling

Nuclear Import of JAK1 Is Mediated by a Classical NLS and Is Required for Survival of Diffuse Large B-cell Lymphoma

DNA-PK: gatekeeper for IKKγ/NEMO nucleocytoplasmic shuttling in genotoxic stress-induced NF-kappaB activation

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