AIDA directly connects sympathetic innervation to adaptive thermogenesis by UCP1

AIDA最早是由林圣彩教授团队首先鉴定和命名的。2007年林圣彩教授团队与孟安明院士团队合作发现AIDA在斑马鱼体轴发育中的功能(Rui, 2007)。2018年，林圣彩教授团队首次发现了AIDA在哺乳动物中的功能，即AIDA介导的内质网降解途径通过降解脂肪合成途径中的关键酶，而限制膳食脂肪在肠道的吸收这一内在抵御肥胖(Luo, 2018)。而本次成果揭示了AIDA在棕色脂肪组织中特定的功能。这些工作将AIDA引入了脂质应激代谢的重要环节，包括脂质吸收和依赖于脂质的产热过程。该论文的共同第一作者为生命科学学院博士生史猛和硕士生黄晓羽，林圣彩教授和林舒勇教授则为共同通讯作者。【Abstract】The sympathetic nervous system–catecholamine–uncoupling protein 1 (UCP1) axis plays an essential role in non-shivering adaptive thermogenesis. However, whether there exists a direct effector that physically connects catecholamine signalling to UCP1 in response to acute cold is unknown. Here we report that outer mitochondrial membrane-located AIDA is phosphorylated at S161 by the catecholamine-activated protein kinase A (PKA). Phosphorylated AIDA translocates to the intermembrane space, where it binds to and activates the uncoupling activity of UCP1 by promoting cysteine oxidation of UCP1.Adipocyte-specific depletion of AIDA abrogates UCP1-dependent thermogenesis, resulting in hypothermia during acute cold exposure. Re-expression of S161A-AIDA, unlike wild-type AIDA, fails to restore the acute cold response in Aida-knockout mice.The PKA–AIDA–UCP1 axis is highly conserved in mammals, including hibernators. Denervation of the sympathetic postganglionic fibres abolishes cold-induced AIDA-dependent thermogenesis. These findings uncover a direct mechanistic link between sympathetic input and UCP1-mediated adaptive thermogenesis.We thank Y. Li, E. Gnaiger, T. Kuwaki, J. R. B. Lighton, E. T. Chouchani and D. Jiang for technical instruction; X. Li and X.-D. Jiang (Core Facility of Biomedical, Xiamen University) for raising the p-S161-AIDA antibody; the Xiamen University Laboratory Animal Center for the mouse in vitro fertilization service and all the other members of S.C.L. laboratory for their technical assistance. This work was supported by grants from the National Key Research and Development Project of China (grant no. 2016YFA0502001) and the National Natural Science Foundation of China (grant nos 31822027, 31871168, 31690101, 91854208 and 82088102), the Fundamental Research Funds for the Central Universities (grant nos 20720190084 and 20720200069), Project ‘111’ sponsored by the State Bureau of Foreign Experts and Ministry of Education of China (grant no. BP2018017), the Youth Innovation Fund of Xiamen (grant no. 3502Z20206028), the Natural Science Foundation of Fujian Province of China (grant no. 2017J01364) and XMU Training Program of Innovation and Entrepreneurship for Undergraduates (grant no. 2019×0666). 该工作得到了厦门大学实验动物中心和生物医学学部仪器平台的重要协助和国家重点研究和发展项目，国家自然科学基金，厦门大学校长基金等的支持

Isolation and Genetic Characterization of Mangshi Virus: A Newly Discovered Seadornavirus of the Reoviridae Family Found in Yunnan Province, China.

Seadornavirus is a genus of viruses in the family Reoviridae, which consists of Banna virus, Kadipiro virus, and Liao ning virus. Banna virus is considered a potential pathogen for zoonotic diseases. Here, we describe a newly discovered Seadornavirus isolated from mosquitos (Culex tritaeniorhynchus) in Yunnan Province, China, which is related to Banna virus, and referred to as Mangshi virus.The Mangshi virus was isolated by cell culture in Aedes albopictus C6/36 cells, in which it replicated and caused cytopathic effects, but not in mammalian BHK-21 or Vero cells. Polyacrylamide gel analysis revealed a genome consisting of 12 segments of double-stranded RNA, with a "6-4-2" pattern in which the migrating bands were different from those of the Banna virus. Complete genome sequencing was performed by full-length amplification of cDNAs. Sequence analysis showed that seven highly conserved nucleotides and three highly conserved nucleotides were present at the ends of the 5'- and 3'-UTRs in each of 12 genome segments. The amino acid identities of Mangshi virus shared with Balaton virus varied from 27.3% (VP11) to 72.3% (VP1) with Banna virus varying from 18.0% (VP11) to 63.9% (VP1). Phylogenetic analysis based on amino acid sequences demonstrated that Mangshi virus is a member of the genus Seadornavirus and is most closely related to, but distinct from, Balaton virus and Banna virus in the genus Seadornavirus of the family Reoviridae.Mangshi virus isolated from mosquitoes (C. tritaeniorhynchus) was identified as a newly discovered virus in the genus Seadornavirus and is phylogenetically close to Banna virus, suggesting that there is genetic diversity of seadornaviruses in tropical and subtropical areas of Southeast Asia

Alignment of the sequence of guanylyltransferases of members of the family <i>Reoviridae</i> in the <i>Mangshi virus</i> (DH13M041) VP3 with other <i>Seadornaviruses</i>.

<p>(a) Alignments of sequences of guanylyltransferases in the vicinity of the motif Kx(I/V/L)S is shown in bold characters. Similar sequences are shaded. (b) Alignments of sequences of guanylyltransferases in the vicinity of the two histidine residues (bold) involved in the guanylyltransferase activity in BAV, KDV, and LNV. Similar sequences are shaded.</p

PCR Identification of DH13M041 virus in the culture supernatant of C6/36 cells using primers derived from segment 12 of BAV by 1% agarose gel electrophoresis (AGE).

<p>1: DH13M127-6; 2: DH13C233-5; 3: DH13M041. 4: Negative control.</p

The identity of amino acid between the Mangshi virus (DH13M041) and other <i>Seadornaviruses</i>.

<p>Note</p><p>*VP1–VP12 corresponding to Seg-1 to Seg-12 of the Mangshi virus (DH13M041).</p><p>The identity of amino acid between the Mangshi virus (DH13M041) and other <i>Seadornaviruses</i>.</p

Electrophoretic migration patterns of the dsRNA of <i>Mangshi virus</i> (DH13M041) as determined by polyacrylamide gel electrophoresis.

<p>1: DH13M127-6 (BAV); 2:C6/36 Cells control; 3: DH13C233-5 (BAV); 4:DH13M041 (<i>Mangshi virus</i>).</p

CPE caused by <i>Mangshi virus</i> (DH13M041) on C6/36 cells 72 h postinoculation (100×).

<p>CPE caused by <i>Mangshi virus</i> (DH13M041) on C6/36 cells 72 h postinoculation (100×).</p

Lengths of dsRNA segments 1 to 12, encoded putative proteins, 5′ and 3′ NCRs of the <i>Mangshi virus</i> (DH13M041) genome.

<p>Lengths of dsRNA segments 1 to 12, encoded putative proteins, 5′ and 3′ NCRs of the <i>Mangshi virus</i> (DH13M041) genome.</p