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Murine Herc6 Plays a Critical Role in Protein ISGylation In Vivo and Has an ISGylation-Independent Function in Seminal Vesicles.

ABSTRACT: ISG15 conjugation (ISGylation) to proteins is a multistep process involving interferon (IFN)-inducible UBE1L (E1), UbcH8 (E2), and ISG15 E3 ligases (E3s). Studies performed over the past several years have shown that ISGylation plays a pivotal role in the host antiviral response against certain viruses. Recent in vitro studies revealed that human Herc5 and mouse Herc6 are major ISG15 E3 ligases, respectively. However, the global function of Herc5/6 proteins in vivo still remains unclear. Here, we report generation and initial characterization of Herc6 knockout mice. Substantial reductions of ISGylation were observed in Herc6-deficient cells after polyinosinic-polycytidylic acid double-stranded RNA injection of mice or IFN treatment of cells. On the other hand, Herc6-deficient cells and wild-type (WT) cells had similar responses to IFN stimulation, Sendai virus (Z strain) infection, and vesicular stomatitis virus infection. These results indicate that Herc6 does not play a critical role in antiviral defense of these viral infections in mice. Interestingly, male Herc6-deficient mice showed seminal vesicle hypertrophy. No such problem was detected in WT and ISG15 activating enzyme Ube1L-deficient mice. These results suggest that in addition to promoting protein ISGylation, Herc6 has a novel and protein ISGylation-independent function in the male reproductive system.

SUBMITTER: Arimoto K

PROVIDER: S-EPMC4426318 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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Murine Herc6 Plays a Critical Role in Protein ISGylation In Vivo and Has an ISGylation-Independent Function in Seminal Vesicles.

Arimoto Kei-ichiro K Hishiki Takayuki T Kiyonari Hiroshi H Abe Takaya T Cheng Chuyi C Yan Ming M Fan Jun-Bao JB Futakuchi Mitsuru M Tsuda Hiroyuki H Murakami Yoshiki Y Suzuki Hideyuki H Zhang Dong-Er DE Shimotohno Kunitada K

Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research 20141119 5

ISG15 conjugation (ISGylation) to proteins is a multistep process involving interferon (IFN)-inducible UBE1L (E1), UbcH8 (E2), and ISG15 E3 ligases (E3s). Studies performed over the past several years have shown that ISGylation plays a pivotal role in the host antiviral response against certain viruses. Recent in vitro studies revealed that human Herc5 and mouse Herc6 are major ISG15 E3 ligases, respectively. However, the global function of Herc5/6 proteins in vivo still remains unclear. Here, w ...[more]

PMID: 25406959

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Project description:Postmenopausal osteoporosis (PMOP) is a severe health issue faced by postmenopausal women. microRNA-128 (miR-128) is associated with aging, inflammatory signaling, and inflammatory diseases, such as PMOP. It has also been reported to modulate in vitro osteogenic/adipogenic differentiation. However, its function in osteoclast formation is unknown. Methods: First, the expression of miR-128 and nuclear factor of activated T cells 1 (Nfatc1, bone resorption master marker) was investigated in bone tissues derived from PMOP patients, while their correlation to each other was also investigated. The levels of miR-128 and Nfatc1 in bone specimens and bone marrow-derived macrophages (BMMs) from mice subjected to ovariectomy (OVX) were also assayed. Next, we employed mice BMMs modified for overexpression and inhibition of miR-128 levels to determine its effect on osteoclast differentiation. Moreover, we generated osteoclastic miR-128 conditional knockout (miR-128Oc-/- ) mice and isolated miR-128 deletion-BMMs to observe its biological function on bone phenotype and osteoclastogenesis in vivo, respectively. The miR-128Oc-/- BMMs were used to explore the downstream regulatory mechanisms using pull-down, luciferase reporter, and western-blotting assays. Finally, the impact of miR-128 deficiency on OVX-induced bone loss in mice was evaluated. Results: The miR-128 level was found to be positively correlated with the increase in Nfatc1 level in mouse/human bone specimens and mouse primary BMMs. In vitro experiments demonstrated miR-128 levels that were dependent on activity of osteoclast differentiation and miR-128 overexpression or inhibition in BMMs significantly increased or decreased osteoclastogenesis, respectively. In vivo, we revealed that osteoclastic miR-128 deletion remarkedly increased bone mass through the inhibition of osteoclastogenesis. Mechanistically, we identified sirtuin 1 (SIRT1) as the direct target of miR-128 at the post-transcriptional level during osteoclast differentiation. Increased levels of SIRT1 reduced nuclear factor κB (NF-κB) activity by decreasing the level of acetylation of Lysine 310, as well as inhibiting tumor necrosis factor-α (Tnf-α) and interleukin 1 (IL-1) expressions. Lastly, osteoclastic deletion of miR-128 significantly suppressed OVX-triggered osteoclastogenesis and exerted a protective effect against bone loss in mice. Conclusions: Our findings reveal a critical mechanism for osteoclastogenesis that is mediated by the miR-128/SIRT1/NF-κB signaling axis, highlighting a possible avenue for the further exploration of diagnostic and therapeutic target molecules in PMOP.

Dataset Information

Murine Herc6 Plays a Critical Role in Protein ISGylation In Vivo and Has an ISGylation-Independent Function in Seminal Vesicles.

Publications

Murine Herc6 Plays a Critical Role in Protein ISGylation In Vivo and Has an ISGylation-Independent Function in Seminal Vesicles.

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