IFN-γ–inducible antiviral responses require ULK1-mediated activation of MLK3 and ERK5

Saleiro, Diana; Blyth, Gavin T.; Kościuczuk, Ewa M.; Ozark, Patrick A.; Majchrzak-Kita, Beata; Arslan, Ahmet Dirim; Fischietti, Mariafausta; Reddy, Neha K.; Horvath, Curt M.; Davis, Roger J.; Fish, Eleanor N.; Platanias, Leonidas C.

doi:10.1126/scisignal.aap9921

Cited by 24 publications

(17 citation statements)

References 76 publications

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“…To understand the molecular underpinnings of betacoronavirus subversion of cellular autophagy, we utilized mouse hepatitis virus-A59 (MHV-A59) as a model and examined its effects on critical components of the canonical autophagy pathway. The serine-threonine kinase ULK1 is an important regulator of cellular autophagy and has recently emerged as an innate immune signaling factor [ 3 , [7] , [8] , [9] ]. The significance of autophagy and innate immune signaling as critical facets of host anti-viral defense, prompted us to investigate the regulation and function of ULK1 during betacoronavirus infection.…”

Section: Resultsmentioning

confidence: 99%

“…The latter facilitates interaction of ULK1 with its various substrates. Autophagy-independent functions of ULK1 have also emerged including the regulation of ER-Golgi trafficking and innate immune signaling [ [7] , [8] , [9] , [10] ]. For example, stimulator of interferon genes (STING), an adaptor of the DNA sensor cyclic GMP-AMP synthase (cGAS), was previously identified as a substrate of ULK1 [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

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The papain-like protease of coronaviruses cleaves ULK1 to disrupt host autophagy

Mohamud¹,

Xue²,

Liu³

et al. 2021

Biochemical and Biophysical Research Communications

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The papain-like protease of coronaviruses cleaves ULK1 to disrupt host autophagy

Mohamud¹,

Xue²,

Liu³

et al. 2021

Biochemical and Biophysical Research Communications

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“…The latter facilitates interaction of ULK1 with its various substrates. Autophagy-independent functions of ULK1 have also emerged including the regulation of ER-Golgi trafficking as well as innate immune signaling (7)(8)(9)(10). For example, stimulator of interferon genes (STING), a critical adaptor of the DNA sensor cyclic GMP-AMP synthase (cGAS), was previously identified as a substrate of ULK1 (11).…”

mentioning

confidence: 99%

The papain-like protease of coronaviruses cleaves ULK1 to disrupt host autophagy

Mohamud

Xue

Liu

et al. 2020

Preprint

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The ongoing pandemic of COVID-19 alongside the outbreaks of SARS in 2003 and MERS in 2012 underscore the significance to understand betacoronaviruses as a global health challenge. SARS-CoV-2, the etiological agent for COVID-19, has infected more than 29 million individuals worldwide with nearly ~1 million fatalities. Understanding how SARS-CoV-2 initiates viral pathogenesis is of the utmost importance for development of antiviral drugs. Autophagy modulators have emerged as potential therapeutic candidates against SARS-CoV-2 but recent clinical setbacks underline the urgent need for better understanding the mechanism of viral subversion of autophagy. Using murine hepatitis virus-A59 (MHV-A59) as a model betacoronavirus, time-course infections revealed a significant loss in the protein level of ULK1, a canonical autophagy regulating serine-threonine kinase, and the concomitant appearance of a possible cleavage fragment. To investigate whether virus-encoded proteases target this protein, we conducted in vitro and cellular cleavage assays and identified ULK1 as a novel bona fide substrate of SARS-CoV-2 papain-like protease (PLpro). Mutagenesis studies discovered that ULK1 is cleaved at a conserved PLpro recognition sequence (LGGG) after G499, separating its N-terminal kinase domain from the C-terminal substrate recognition region. Consistent with this, over-expression of SARS-CoV-2 PLpro is sufficient to impair starvation-induced canonical autophagy and disrupt formation of ULK1-ATG13 complex. Finally, we demonstrated a dual role for ULK1 in MHV-A59 replication, serving a pro-viral functions during early replication that is inactivated at late stages of infection. In conclusion, our study identified a new mechanism by which PLpro of betacoronaviruses induces viral pathogenesis by targeting cellular autophagic pathway.

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“…CAS10138 and no. VSGH10142-246477203, GE Healthcare Dharmacon), as previously described 48 . Lack of ULK1 protein in ULK1 KO KT-1 cells was confirmed by immunobloting analysis.…”

Section: Methodsmentioning

confidence: 99%

Discovery of a signaling feedback circuit that defines interferon responses in myeloproliferative neoplasms

et al. 2022

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Interferons (IFNs) are key initiators and effectors of the immune response against malignant cells and also directly inhibit tumor growth. IFNα is highly effective in the treatment of myeloproliferative neoplasms (MPNs), but the mechanisms of action are unclear and it remains unknown why some patients respond to IFNα and others do not. Here, we identify and characterize a pathway involving PKCδ-dependent phosphorylation of ULK1 on serine residues 341 and 495, required for subsequent activation of p38 MAPK. We show that this pathway is essential for IFN-suppressive effects on primary malignant erythroid precursors from MPN patients, and that increased levels of ULK1 and p38 MAPK correlate with clinical response to IFNα therapy in these patients. We also demonstrate that IFNα treatment induces cleavage/activation of the ULK1-interacting ROCK1/2 proteins in vitro and in vivo, triggering a negative feedback loop that suppresses IFN responses. Overexpression of ROCK1/2 is seen in MPN patients and their genetic or pharmacological inhibition enhances IFN-anti-neoplastic responses in malignant erythroid precursors from MPN patients. These findings suggest the clinical potential of pharmacological inhibition of ROCK1/2 in combination with IFN-therapy for the treatment of MPNs.

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IFN-γ–inducible antiviral responses require ULK1-mediated activation of MLK3 and ERK5

Cited by 24 publications

References 76 publications

The papain-like protease of coronaviruses cleaves ULK1 to disrupt host autophagy

The papain-like protease of coronaviruses cleaves ULK1 to disrupt host autophagy

The papain-like protease of coronaviruses cleaves ULK1 to disrupt host autophagy

Discovery of a signaling feedback circuit that defines interferon responses in myeloproliferative neoplasms

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