The emerging roles of MARCH8 in viral infections: A double-edged Sword

Yu, Changqing; Liu, Qiang; Zhao, Zhuo; Zhai, Jingbo; Xue, Mengzhou; Tang, Yan-Dong; Wang, Chengbao; Zheng, Chunfu

doi:10.1371/journal.ppat.1011619

Cited by 10 publications

(7 citation statements)

References 72 publications

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“…As E7 is required for viral replication, this finding suggests that MARCHF8 contributes to HPV infection and persistence. Likewise, recent studies have shown that MARCHF8 supports infection of several human viruses, including HCV, dengue, and Zika ( 66 ). Particularly, MARCHF8 induces the polyubiquitination of the HCV nonstructural2 protein that mediates binding to ESCRT0 and assembling viral envelope ( 67 , 68 ).…”

Section: Discussionmentioning

confidence: 99%

The membrane-associated ubiquitin ligase MARCHF8 stabilizes the human papillomavirus oncoprotein E7 by degrading CUL1 and UBE2L3 in head and neck cancer

Khalil,

Yang,

et al. 2024

J Virol

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The human papillomavirus (HPV) oncoprotein E7 is a relatively short-lived protein required for HPV-driven cancer development and maintenance. E7 is degraded through ubiquitination mediated by cullin 1 (CUL1) and the ubiquitin-conjugating enzyme E2 L3 (UBE2L3). However, E7 proteins are maintained at high levels in most HPV-positive cancer cells. A previous proteomics study has shown that UBE2L3 and CUL1 protein levels are increased by the knockdown of the E3 ubiquitin ligase membrane-associated ring-CH-type finger 8 (MARCHF8). We have recently demonstrated that HPV16 upregulates MARCHF8 expression in HPV-positive keratinocytes and head and neck cancer (HPV+ HNC) cells. Here, we report that MARCHF8 stabilizes the HPV16 E7 protein by degrading the components of the S-phase kinase-associated protein 1-CUL1-F-box ubiquitin ligase complex in HPV+ HNC cells. We found that MARCHF8 knockdown in HPV+ HNC cells drastically decreases the HPV16 E7 protein level while increasing the CUL1 and UBE2L3 protein levels. We further revealed that the MARCHF8 protein binds to and ubiquitinates CUL1 and UBE2L3 proteins and that MARCHF8 knockdown enhances the ubiquitination of the HPV16 E7 protein. Conversely, the overexpression of CUL1 and UBE2L3 in HPV+ HNC cells decreases HPV16 E7 protein levels and suppresses tumor growth in vivo . Our findings suggest that HPV-induced MARCHF8 prevents the degradation of the HPV16 E7 protein in HPV+ HNC cells by ubiquitinating and degrading CUL1 and UBE2L3 proteins. IMPORTANCE Since human papillomavirus (HPV) oncoprotein E7 is essential for virus replication; HPV has to maintain high levels of E7 expression in HPV-infected cells. However, HPV E7 can be efficiently ubiquitinated by a ubiquitin ligase and degraded by proteasomes in the host cell. Mechanistically, the E3 ubiquitin ligase complex cullin 1 (CUL1) and ubiquitin-conjugating enzyme E2 L3 (UBE2L3) components play an essential role in E7 ubiquitination and degradation. Here, we show that the membrane ubiquitin ligase membrane-associated ring-CH-type finger 8 (MARCHF8) induced by HPV16 E6 stabilizes the E7 protein by degrading CUL1 and UBE2L3 and blocking E7 degradation through proteasomes. MARCHF8 knockout restores CUL1 and UBE2L3 expression, decreasing E7 protein levels and inhibiting the proliferation of HPV-positive cancer cells. Additionally, overexpression of CUL1 or UBE2L3 decreases E7 protein levels and suppresses in vivo tumor growth. Our results suggest that HPV16 maintains high E7 protein levels in the host cell by inducing MARCHF8, which may be critical for cell proliferation and tumorigenesis.

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Section: Discussionmentioning

confidence: 99%

The membrane-associated ubiquitin ligase MARCHF8 stabilizes the human papillomavirus oncoprotein E7 by degrading CUL1 and UBE2L3 in head and neck cancer

Khalil,

Yang,

et al. 2024

J Virol

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show abstract

“…As E7 is required for viral replication, this finding suggests that MARCHF8 contributes to HPV infection and persistence. Likewise, recent studies have shown that MARCHF8 supports infection of several human viruses, including HCV, dengue, and Zika (66). Particularly, MARCHF8 induces the polyubiquitination of the HCV nonstructural2 (NS2) protein that mediates binding to ESCRT0 and assembling viral envelope (67, 68).…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, MARCHF8 facilitates HIV infection by ubiquitinating and degrading Tetherin independent of Vpu (69). In contrast, MARCHF8 is also known as an antiviral restriction factor (66). MARCHF8 targets several viral envelope glycoproteins to inhibit infections of HIV, vesicular stomatitis virus, rabies virus, lymphocytic choriomeningitis virus, SARS-CoV, Chikungunya virus, and Ross River virus (70–72).…”

Section: Discussionmentioning

confidence: 99%

The membrane-associated ubiquitin ligase MARCHF8 stabilizes the human papillomavirus oncoprotein E7 by degrading CUL1 and UBE2L3 in head and neck cancer

Khalil,

Yang,

et al. 2023

Preprint

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The human papillomavirus (HPV) oncoprotein E7 is a relatively short-lived protein required for HPV-driven cancer development and maintenance. E7 is degraded through ubiquitination mediated by cullin 1 (CUL1) and the ubiquitin-conjugating enzyme E2 L3 (UBE2L3). However, E7 proteins are maintained at high levels in most HPV-positive cancer cells. A previous proteomics study has shown that UBE2L3 and CUL1 protein levels are increased by the knockdown of the E3 ubiquitin ligase membrane-associated ring-CH-type finger 8 (MARCHF8). We have recently demonstrated that HPV upregulates MARCHF8 expression in HPV-positive keratinocytes and head and neck cancer (HPV+ HNC) cells. Here, we report that MARCHF8 stabilizes the E7 protein by degrading the components of the SKP1-CUL1-F-box (SCF) ubiquitin ligase complex in HPV+ HNC cells. We found thatMARCHF8knockdown in HPV+ HNC cells drastically decreases the E7 protein level while increasing the CUL1 and UBE2L3 protein levels. We further revealed that the MARCHF8 protein binds to and ubiquitinates CUL1 and UBE2L3 proteins and that MARCHF8 knockdown enhances the ubiquitination of the E7 protein. Conversely, the overexpression of CUL1 and UBE2L3 in HPV+ HNC cells decreases E7 protein levels and suppresses tumor growth in vivo. Our findings suggest that HPV-induced MARCHF8 prevents the degradation of the E7 protein in HPV+ HNC cells by ubiquitinating and degrading CUL1 and UBE2L3 proteins.IMPORTANCESince HPV oncoprotein E7 is essential for virus replication, HPV has to maintain high levels of E7 expression in HPV-infected cells. However, HPV E7 can be efficiently ubiquitinated by a ubiquitin ligase and degraded by proteasomes in the host cell. Mechanistically, the components of the E3 ubiquitin ligase complex CUL1 and UBE2L3 play an essential role in E7 ubiquitination and degradation. Here, we show that the membrane ubiquitin ligase MARCHF8 induced by HPV E6 stabilizes the E7 protein by degrading CUL1 and UBE2L3 and blocking E7 degradation through proteasomes. MARCHF8 knockout restores CUL1 and UBE2L3 expression, decreasing E7 protein levels and inhibiting the proliferation of HPV-positive cancer cells. Additionally, overexpression of CUL1 or UBE2L3 decreases E7 protein levels and suppresses in vivo tumor growth. Our results suggest that HPV maintains high E7 protein levels in the host cell by inducing MARCHF8, which may be critical for cell proliferation and tumorigenesis.

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“…Human MARCH1, MARCH2, and MARCH8 are highly expressed in MDMs, 24,26 which are critical infection targets of EBOV. Thus, to effectively replicate in MDMs, whether EBOV needs to overcome these human MARCH proteins' restriction deserves further investigation 46 …”

Section: Discussionmentioning

confidence: 99%

“…Thus, to effectively replicate in MDMs, whether EBOV needs to overcome these human MARCH proteins' restriction deserves further investigation. 46…”

Section: March1 and March2 Inhibited Furin-cleavage Of Ebov Gpmentioning

confidence: 99%

Human MARCH1, 2, and 8 block Ebola virus envelope glycoprotein cleavage via targeting furin P domain

Yu,

Bai,

Tan

et al. 2024

Journal of Medical Virology

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Membrane‐associated RING‐CH (MARCH) family proteins were recently reported to inhibit viral replication through multiple modes. Previous work showed that human MARCH8 blocked Ebola virus (EBOV) glycoprotein (GP) maturation. Our study here demonstrates that human MARCH1 and MARCH2 share a similar pattern to MARCH8 in restricting EBOV GP‐pseudotyped viral infection. Human MARCH1 and MARCH2 retain EBOV GP at the trans‐Golgi network, reduce its cell surface display, and impair EBOV GP‐pseudotyped virions infectivity. Furthermore, we uncover that the host proprotein convertase furin could interact with human MARCH1/2 and EBOV GP intracellularly. Importantly, the furin P domain is verified to be recognized by MARCH1/2/8, which is critical for their blocking activities. Besides, bovine MARCH2 and murine MARCH1 also impair EBOV GP proteolytic processing. Altogether, our findings confirm that MARCH1/2 proteins of different mammalian origins showed a relatively conserved feature in blocking EBOV GP cleavage, which could provide clues for subsequent MARCHs antiviral studies and may facilitate the development of novel strategies to antagonize enveloped virus infection.

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The emerging roles of MARCH8 in viral infections: A double-edged Sword

Cited by 10 publications

References 72 publications

The membrane-associated ubiquitin ligase MARCHF8 stabilizes the human papillomavirus oncoprotein E7 by degrading CUL1 and UBE2L3 in head and neck cancer

The membrane-associated ubiquitin ligase MARCHF8 stabilizes the human papillomavirus oncoprotein E7 by degrading CUL1 and UBE2L3 in head and neck cancer

The membrane-associated ubiquitin ligase MARCHF8 stabilizes the human papillomavirus oncoprotein E7 by degrading CUL1 and UBE2L3 in head and neck cancer

Human MARCH1, 2, and 8 block Ebola virus envelope glycoprotein cleavage via targeting furin P domain

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