The prognostic value of 19S ATPase proteasome subunits in acute myeloid leukemia and other forms of cancer

Tychhon, Boranai; Allen, Jesse; Gonzalez, Mayra A.; Olivas, Idaly M.; Solecki, Jonathan P.; Keivan, Mehrshad; Velazquez, Vanessa V.; McCall, Emily B.; Tapia, Desiree N.; Rubio, Andres J.; Jordan, Connor; Elliott, David; Eiring, Anna M.

doi:10.3389/fmed.2023.1209425

“…This raises the interesting possibility that either bacterial effector function or inactivation of the host targets of effectors might enhance the replication of oncolytic viruses in cancer cell types normally refractory to these viruses. Importantly, both SHOC2 and PSMC1 are often up-regulated in human malignancies have been linked to cellular transformation and tumor metastasis [93][94][95].…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, gain-of-function SHOC2 mutations have been linked to RASopathies, a group of clinical pathologies associated with dysregulated RAS/MAPK signaling such as Noonan syndrome and patients with these syndromes are predisposed to certain cancers [96][97][98]. Moreover, elevated SHOC2 and PSMC1 expression has been associated with poorer clinical outcomes among cancer patients [95,98]. Given the common upregulation of SHOC2 and PSMC1 in transformed cells, they may be particularly relevant to the reported refractory nature of some tumors to oncolytic VSV strains replication [70,74].…”

Section: Discussionmentioning

confidence: 99%

“…Importantly, both SHOC2 and PSMC1 are often up-regulated in human malignancies have been linked to cellular transformation and tumor metastasis [93–95]. Indeed, gain-of-function SHOC2 mutations have been linked to RASopathies, a group of clinical pathologies associated with dysregulated RAS/MAPK signaling such as Noonan syndrome and patients with these syndromes are predisposed to certain cancers [96–98]. Moreover, elevated SHOC2 and PSMC1 expression has been associated with poorer clinical outcomes among cancer patients [95, 98].…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Exploiting Bacterial Effector Proteins to Uncover Evolutionarily Conserved Antiviral Host Machinery

Embry,

Baggett,

Heisler

et al. 2024

Preprint

1

0

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Arboviruses are a diverse group of insect-transmitted pathogens that pose global public health challenges. Identifying evolutionarily conserved host factors that combat arbovirus replication in disparate eukaryotic hosts is important as they may tip the balance between productive and abortive viral replication, and thus determine virus host range. Here, we exploit naturally abortive arbovirus infections that we identified in lepidopteran cells and use bacterial effector proteins to uncover host factors restricting arbovirus replication. Bacterial effectors are proteins secreted by pathogenic bacteria into eukaryotic hosts cells that can inhibit antimicrobial defenses. Since bacteria and viruses can encounter common host defenses, we hypothesized that some bacterial effectors may inhibit host factors that restrict arbovirus replication in lepidopteran cells. Thus, we used bacterial effectors as molecular tools to identify host factors that restrict four distinct arboviruses in lepidopteran cells. By screening 210 effectors encoded by seven different bacterial pathogens, we identify six effectors that individually rescue the replication of all four arboviruses. We show that these effectors encode diverse enzymatic activities that are required to break arbovirus restriction. We further characterizeShigella flexneri-encoded IpaH4 as an E3 ubiquitin ligase that directly ubiquitinates two evolutionarily conserved proteins, SHOC2 and PSMC1, promoting their degradation in insect and human cells. We show that depletion of either SHOC2 or PSMC1 in insect or human cells promotes arbovirus replication, indicating that these are ancient virus restriction factors conserved across invertebrate and vertebrate hosts. Collectively, our study reveals a novel pathogen-guided approach to identify conserved antimicrobial machinery, new effector functions, and conserved roles for SHOC2 and PSMC1 in virus restriction.Author SummaryMicrobial pathogens such as viruses and bacteria encounter diverse host cell responses during infection. While viruses possess antagonists to counter these responses in natural host species, their replication can be restricted in unnatural host cells where their antagonists are ineffective. Bacteria also employ a diverse repertoire of immune evasion proteins known as “effectors” that can inhibit antimicrobial responses found in invertebrate and vertebrate hosts. In this study, we hypothesized that some bacterial effectors may target host immunity proteins that restrict both bacteria and viruses. To test this hypothesis, we screened a bacterial effector library comprising 210 effectors from seven distinct bacterial pathogens for their ability to rescue the replication of four viruses in insect cells that are normally non-permissive to these viruses. Though numerous effectors were identified to rescue the replication of each virus, the uncharacterized IpaH4 protein encoded by the human pathogenShigella flexneriwas able to rescue all four viruses screened. We discovered that IpaH4 enhances arbovirus replication in both restrictive insect and permissive human cells by directly targeting two novel, evolutionarily conserved antiviral host proteins, SHOC2 and PSMC1, for degradation. Our study establishes bacterial effectors as valuable tools for identifying critical antimicrobial machinery employed by eukaryotic hosts.

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“…This raises the interesting possibility that either bacterial effector function or inactivation of the host targets of effectors might enhance the replication of oncolytic viruses in cancer cell types normally refractory to these viruses. Importantly, both SHOC2 and PSMC1 are often up-regulated in human malignancies and have been linked to cellular transformation and tumor metastasis [96][97][98]. Indeed, gain-of-function SHOC2 mutations have been linked to RASopathies, a group of clinical pathologies associated with dysregulated RAS/MAPK signaling such as Noonan syndrome and patients with these syndromes are predisposed to certain cancers [99][100][101].…”

Section: Plos Pathogensmentioning

confidence: 99%

“…Indeed, gain-of-function SHOC2 mutations have been linked to RASopathies, a group of clinical pathologies associated with dysregulated RAS/MAPK signaling such as Noonan syndrome and patients with these syndromes are predisposed to certain cancers [99][100][101]. Moreover, elevated SHOC2 and PSMC1 expression has been associated with poorer clinical outcomes among cancer patients [98,101]. Given the common upregulation of SHOC2 and PSMC1 in transformed cells, they may be particularly relevant to the reported refractory nature of some tumors to oncolytic VSV strains replication [69,73].…”

Section: Plos Pathogensmentioning

confidence: 99%

Exploiting bacterial effector proteins to uncover evolutionarily conserved antiviral host machinery

Embry,

Baggett,

Heisler

et al. 2024

PLoS Pathog

3

0

View full text Add to dashboard Cite

Arboviruses are a diverse group of insect-transmitted pathogens that pose global public health challenges. Identifying evolutionarily conserved host factors that combat arbovirus replication in disparate eukaryotic hosts is important as they may tip the balance between productive and abortive viral replication, and thus determine virus host range. Here, we exploit naturally abortive arbovirus infections that we identified in lepidopteran cells and use bacterial effector proteins to uncover host factors restricting arbovirus replication. Bacterial effectors are proteins secreted by pathogenic bacteria into eukaryotic hosts cells that can inhibit antimicrobial defenses. Since bacteria and viruses can encounter common host defenses, we hypothesized that some bacterial effectors may inhibit host factors that restrict arbovirus replication in lepidopteran cells. Thus, we used bacterial effectors as molecular tools to identify host factors that restrict four distinct arboviruses in lepidopteran cells. By screening 210 effectors encoded by seven different bacterial pathogens, we identify several effectors that individually rescue the replication of all four arboviruses. We show that these effectors encode diverse enzymatic activities that are required to break arbovirus restriction. We further characterize Shigella flexneri-encoded IpaH4 as an E3 ubiquitin ligase that directly ubiquitinates two evolutionarily conserved proteins, SHOC2 and PSMC1, promoting their degradation in insect and human cells. We show that depletion of either SHOC2 or PSMC1 in insect or human cells promotes arbovirus replication, indicating that these are ancient virus restriction factors conserved across invertebrate and vertebrate hosts. Collectively, our study reveals a novel pathogen-guided approach to identify conserved antimicrobial machinery, new effector functions, and conserved roles for SHOC2 and PSMC1 in virus restriction.

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Therapeutic approaches targeting oncogenic proteins in myeloid leukemia: challenges and perspectives

Yan,

Kang,

Zhang

et al. 2024

Expert Opinion on Therapeutic Targets

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The prognostic value of 19S ATPase proteasome subunits in acute myeloid leukemia and other forms of cancer

Cited by 5 publications

References 77 publications

Exploiting Bacterial Effector Proteins to Uncover Evolutionarily Conserved Antiviral Host Machinery

Exploiting Bacterial Effector Proteins to Uncover Evolutionarily Conserved Antiviral Host Machinery

Exploiting bacterial effector proteins to uncover evolutionarily conserved antiviral host machinery

Therapeutic approaches targeting oncogenic proteins in myeloid leukemia: challenges and perspectives

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