编 者 按

1月22日，美国麻省理工学院份子妄想试验室（Laboratory of Molecular Architecture）首席钻研员（Head）张曙光向迷信网提供了一份当天致饶毅教授的光V钢被简牍，就后者21日晚在其总体公号“饶议迷信”上“正式揭发林-裴(1999)论文涉嫌学术不端”一文宣告意见。毅对于裴

此外，论文受质疑论文的鸣往3位第一作者（通讯作者为裴钢院士）向迷信网提供了以及这篇论文相关的综述质料。

学术争鸣在迷信睁开历程中具备可有可无的事迷熏染。作为“全天下华人迷信家社区”，信网迷信网特宣告各方意见，张曙质疑愿望能增长彼此间的光V钢被理性对于话，发挥好“谋求不对于、毅对于裴松散治学”的论文务实肉体。

1. 张曙光致饶毅简牍全文

饶毅博士：

我对于您针对于裴钢博士及其共事1999年在PNAS上宣告的鸣往论文提出控诉却不子细浏览相关迷信文献感应颇为震撼。作为一位在加州大学旧金山分校以及哈佛大学受过正规科研磨炼的事迷迷信家，您的信网控诉不光是过错的，而且也不对于妨碍控诉的张曙质疑念头妨碍批注或者证实。

为了反对于裴钢博士的迷信科研下场，请您参考近多少年我在麻省理工学院的钻研下场使命。咱们的钻研服从已经以“Non-full-length Water-Soluble CXCR4QTY and CCR5QTY Chemokine Receptors: Implication for Overlooked Truncated but Functional Membrane Receptors” 为题，2020年报道宣告在Cell子刊iScience(Cell Press)上。咱们的论文不光证明了凌堃等人1999年报道在PNAS 上的“Five-transmembrane domains appear sufficient for a G protein-coupled receptor: Functional five-transmembrane domain chemokine receptors”使掷中陈说的服从，也清晰地表明，惟独2个或者3个跨膜片断的CXCR4以及CCR5突变体可能展现出配体散漫活性、可能定位到细胞质膜上、并可能妨碍细胞信号转导。咱们的数据以及其余人钻研组的使命都直接反对于了凌堃等人在其1999年PNAS论文中的论断。实际上，咱们的钻研使命美全是从差距的钻研角度对于相同的卵白质妨碍的。

看来您也没无关注到Helen Wise博士的综述论文，“ G卵白偶联受体的高度截短的剪接变体所起的熏染”。J. Mol. Signal., 7, 13 (2012)。在这篇综述文章中，Wise博士列出了良多此类截短但具备功能个别的受体。使人惊惶的是，您居然可能在残缺不浏览文献的情景下提出了如斯严正的控诉。

您在不熟习相关迷信文献的情景下提出的控诉，在迷信以及伦理上都是残缺不负责任的。作为在加州大学旧金山分校以及哈佛大学受过磨炼的迷信家、华盛顿大学以及西北大学的教授，您理当知道，任何控诉都必需基于实用的迷信证据。您冒失的控诉，对于被控诉者，特意是年迈迷信家的迷信声誉以及科研生涯组成极大伤害。

我以为您的批评残缺不道理，您必需真挚地向裴钢博士及其共事赔罪。

有据可查的科研不妥行动严正伤害了中国的迷信声誉以及天下位置，可是，所有控诉以及控诉都必需基于事实。我起劲反对于在中国各个层面将学生以及院士的科研不妥行动赶尽扑灭。

假如您有任何疑难，请分割我。

张曙光博士

2. 受质疑论文3位一作提供的对于1999年论文相关综述质料

对于G卵白偶联截短受体的国内外钻研妨碍陈说

凌堃（梅奥医学中间生化与份子生物学系 副教授）、

赵简（上海科技大学免疫化学钻研所 钻研员）、

王平（同济大学医学院 教授）

在植物细胞膜上表白的种种信号受体中，G卵白偶联受体（GPCR）家族可能说是成员最为泛滥，功能最为多样，扩散最为普遍的家族。当初已经确认的人类GPCR有1265个，单个细胞规范个别表白一百种以上的GPCR，这些信号受体经由激活细胞中的种种G卵白，影响着当初已经知的人类心理病理的所有方面；响应的，至少有50％的上市药物靶标是GPCR家族成员。

以往巨匠个别以为，7次跨膜妄想对于GPCR来说是一种普遍适用的妄想，可能最有利于G卵白以及卑劣信号的激活。可是自90年月初起，历年来的钻研揭示了一些老例，揭示少于7次跨膜的某些GPCR家族成员的变体以及某些非7次跨膜妄想的受体，也具备差距水平的GPCR功能。

其中，咱们1999年宣告在PNAS的钻研运用GPCR家族成员CCR5以及CXCR4作为模子，提供了较早的证据（Ling K, Wang P, Zhao J, Wu YL, Cheng ZJ, Wu GX, Hu W, Ma L, Pei G. Five-transmembrane domains appear sufficient for a G protein-coupled receptor: functional five-transmembrane domain chemokine receptors. Proc Natl Acad Sci U S A. 1999; 96:7922-7）。

在咱们的钻研宣告之后，更多相似的老例被陆续发现，搜罗一些GPCR经由转录剪切而发生的做作跨膜区缺失变体（搜罗5次跨膜及其余规范的跨膜区缺失），为钻研GPCR妄想功能而酬谢制作的跨膜区缺失变体， 以及一些非7次跨膜的其余种类的膜受体，这些非典型的GPCR受体仍能介导G卵白卑劣信号。

这些服从表明，各个跨膜区的紧张性在差距的GPCR中可能有很大的差距，5次跨膜或者其余少于7次跨膜的GPCR可能经由组成同源或者异源多聚体的方式，至少部份运用散漫配体并激活卑劣G卵白信号的功能。

这些钻研展现，特定GPCR家族成员具备差距于普适纪律的特色，揭示了细胞调节G卵白信号的别致方式，有助于咱们清晰重大的细胞心理病理的份子机制，拟订与之对于应的特异的干涉措施，为药物研发等揭示新的思绪。

（一）做作存在的GPCR 少于7次跨膜截短变体

1. G卵白偶联受体bacteriorhodopsin存在缺失第1以及第2跨膜区的5次跨膜做作变体，这个5跨膜变体在体外零星中也可能表白在细胞膜上。（Theodore WK and Donald ME. Bacteriorhodopsin Can Be Refolded from Two Independently Stable Transmembrane Helices and the Complementary Five-Helix Fragment. Biochemistry. 1992; 31:6144-51.）

2. G卵白偶联受体mGluR1需要组成二聚体来激活G卵白信号通路。幽默的是，这个钻研表明，缺失第1以及第2. 跨膜区不影响这种二聚体的组成。（Belenikin MS, Costantino G, Palyulin VA, Pellicciari R, Zefirov NS. Molecular modeling of the mGluR1 metabotropic glutamate receptor transmembrane domain and construction of the model of its dimer. Dokl. Biochem. Biophys. 2003; 393:341-5.）

3. 编码GnRH-II受体的基因除了表白家养型7次跨膜受体外，也可能发生5次跨膜的做作截短变体。这一5跨膜GnRH-II受体缺失第1以及第2跨膜区，但仍能照应配体的特异性宽慰，发挥受体功能。（Neill JD, Musgrove LC, Duck LW. Newly recognized GnRH receptors: function and relative role. Trends Endocrinol Metab. 2004; 15(8):383-92.）

4. 二型神经降压素NTS2 受体是一种G卵白偶联受体，其编码基因可能发生5次跨膜的做作变体。该变体展现与家养型NTS2受体同样的机关/器官表白谱，并经由组成同源或者异源二聚体以及多聚体实现受体功能。（Perron A, Sarret P, Gendron L, Stroh T, Beaudet A. Identification and functional characterization of a 5-transmembrane domain variant isoform of the NTS2 neurotensin receptor in rat central nervous system. J. Biol. Chem. 2005; 280(11):10219-27. ）

5. 神经内渗透受体VPAC1以及VPAC2是G卵白偶联受体，其编码基因可能发生缺失第6第7跨膜区的5次跨膜做作变体。该变体展现与家养型受体差距的细胞/机关表白谱，仍能散漫配体并运用部份受体功能。（Bokaei PB, Ma XZ, Byczynski B, Keller J, Sakac D, Fahim S, Branch DR. Identification and characterization of five-transmembrane isoforms of human vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide receptors. Genomics 2006; 88:791-800.）

6. 人类妨碍抑素SST5受体是一种G卵白偶联受体。这个钻研发现，SST5受体基因可能发生惟独5个跨膜区的依然具备功能的做作变体。（Durán-Prado M, Gahete MD, Martínez-Fuentes AJ, Luque RM, Quintero A, Webb SM, Benito-López P, Leal A, Schulz S, Gracia-Navarro F, Malagón MM, Castaño JP. Identification and characterization of two novel truncated but functional isoforms of the somatostatin receptor subtype 5 differentially present in pituitary tumors. J. Clin. Endocrinol Metab. 2009; 94(7):2634-43. ）

7. Castaño钻研组的后续钻研发现，SST5受体基因还可能发生惟独4，2，或者1个跨膜区的做作截短变体。比力7次跨膜的家养型受体，这些跨膜区缺失的变体展现出相似的表白水暖以及功能。（Córdoba-Chacón J, Gahete MD, Duran-Prado M, Pozo-Salas AI, Malagón MM, Gracia-Navarro F, Kineman RD, Luque RM, Castaño JP. Identification and characterization of new functional truncated variants of somatostatin receptor subtype 5 in rodents. Cell Mol. Life Sci. 2010; 67(7):1147-63.）

8. 人家养型GHS受体基因除了发生7次跨膜的GPCR外，还可能发生5次跨膜截短受体。这个五次跨膜的GHS受体可能与神经降压素NTS1受体组成异源受体二聚物，发生新的心理熏染，这一发现可能为抑制非小细胞肺癌细胞妨碍，提供了全新的药物靶标。（Navarro G, Aguinaga D, Angelats E, Medrano M, Moreno E, Mallol J, Cortés A, Canela EI, Casadó V, McCormick PJ, Lluís C, Ferré S. A Significant Role of the Truncated Ghrelin Receptor GHS-R1b in Ghrelin-induced Signaling in Neurons. J Biol Chem. 2016; 291(25): 13048–13062.）

9. Prokineticin receptor 2（PKR2）是一种GPCR，经由Gq、Gi、以及Gs分说调控胞内钙转运、STAT3激活、以及cAMP分解。钻研发现PKR2基因转录产物存在做作剪切变体，发生一个缺失第1-3跨膜区的截短变体。这个变体依然能在细胞膜上表白，并保存了却合配体并激活Gq以及Gs的功能。（Lattanzia R, Mafteib D, Fulloneb MR, Miele R. Identification and characterization of Prokineticin receptor 2 splicing variant and its modulation in an animal model of Alzheimers disease. Neuropeptides 2019; 73: 49–56.）

（二）为钻研妄想功能关连而酬谢制作的缺失跨膜区或者胞内环的GPCR截短变体

1. 在钻研中，Chelli以及 Alizon酬谢妄想制作了多种差距跨膜区缺失的CCR5变体，其中有一些依然表白在细胞膜上并利勤勉用。这一使命的服从表明，第一、第2跨膜区不是CCR5利勤勉用所必需的。（Chelli M and Alizon M. Determinants of the trans-dominant Negative Effect of Truncated Forms of the CCR5 Chemokine Receptor. J. Biol. Chem. 2002; 276(50):46975-82.）

2. Biard-Piechaczy课题组钻研了酬谢妄想制作的差距胞内环缺失的CXCR4截短变体，其服从表明第一胞内环不是CXCR4被配体激活所必需的，这一点与咱们的服从不同。（Roland J， Murphy BJ, Robert-Hebmann V, Delauzun V, Nye KE, Devaux C, Biard-Piechaczyk M. Role of the intracellular domains of CXCR4 in SDF-1-mediated signaling. Blood 2003; 101:399-406.）

3. 由于可能组成二聚体或者多聚体，缺失差距跨膜区的多种5次跨膜或者3次跨膜的CXCR4变体可能在细胞膜概况个别表白。（Hamatake M, Aoki T, Futahashi Y, Urano E, Yamamoto N, Komano J. Ligand-independent higher-order multimerization of CXCR4, a G-protein-coupled chemokine receptor involved in targeted metastasis. Cancer Sci. 2009; 100(1):95-102.）

4. 张曙光钻研组发现多少种截短的趋化因子受体，即远少于七次跨膜的CXCR4以及CCR5受体突变体，并非毫无功能，而是可能与做作配体结并吞调节部份细胞功能，从而为药物研发、免疫疗法以及仿生器件研发等带来了新的思绪。（Qing R, Tao F, Chatterjee P, Yang G, Han Q, Chung H, Ni J, Suter BP, Kubicek J, Maertens B, Schubert T, Blackburn C, Zhang S. Non-full-length Water-Soluble CXCR4QTY and CCR5QTY Chemokine Receptors: Implication for Overlooked Truncated but Functional Membrane Receptors. iScience. 2020; 23:101670.）

（三）可能激活G卵白信号通路的非七次跨膜的其余膜受体

1. 家喻户晓，妨碍因子受体是一个单次跨膜受体。该钻研发现，这个单次跨膜受体可能散漫G卵白，并激活G卵白信号通路。（Liang MN and Garrison JC. The epidermal growth factor receptor is coupled to a pertussis toxin-sensitive guanine nucleotide regulatory protein in rat hepatocytes. J. Biol. Chem. 1991; 266(20):1342-9.）

2. CD47是一个5 次跨膜的膜卵白，钻研表明，CD47也可能结并吞激活G卵白及其卑劣信号。（Rebres RA, Vaz LE, Green JM, Brown EJ. Normal ligand binding and signaling by CD47 (integrin-associated protein) requires a long-range disulfide bond between the extracellular and membrane-spanning domains. J. Biol. Chem. 2001; 276(37):34607-16.）

3. 多囊卵白1 是一个11次跨膜的卵白，Calvet钻研组初次发现，这个11次跨膜卵白可能散漫G卵白，并激活G卵白及其卑劣信号通路。（Parnell SC, Magenheimer BS, Maser RL, Zien CA, Frischauf AM, Calvet JP. J Biol Chem. 2002; 277(22):19566-72.）

4. Cook钻研组的钻研展现，Toll-like receptor 4作为一个单次跨膜的受体，也能激活G卵白信号通路。（Fan H, Peck OM, Tempel GE, Halushka PV, Cook JA. Toll-like receptor 4 coupled GI protein signaling pathways regulate extracellular signal-regulated kinase phosphorylation and AP-1 activation independent of NFkB activation. Shock. 2004; 22(1):57-62. ）

（四）总结

以上钻研服从清晰地表明，GPCR家族成员除了具备7次跨膜妄想以及激活G卵白这两个特色之外，每一个成员还具备自己的配合特色，这一点是由它们颇为差距的氨基酸一级序列所反对于的。对于GPCR截短变体的钻研，特意是对于其在特定细胞或者机关的心理病理历程的钻研，有可能填补老例GPCR受体的钻研，为相关人类疾病提供新的药物靶标。

为此咱们需要子细地将每一种GPCR视为一个配合的实例，详细赴任异细胞、机关、代谢实时空的维度上，子细评估它们对于细胞心理病理历程及药理反映的意思。

除了此之外，其余非7次跨膜妄想的膜受体对于激活G卵白信号的贡献也不可轻忽，这些受体可能对于GPCR的功能起到填补以及调节熏染，清晰其中的份子机制有可能为咱们的药物妄想另辟蹊径，提供斩新的思绪。

（五）附言

1999年宣告在PNAS对于五跨膜突变受体钻研的援用情景汇总：

总援用次数：84次；其中自引：8次，他引：76次；综述类援用：27次，研品评辩说文援用：57次；非英语论文援用：7次；质疑援用：0次。

附-援用清单：

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2. Belenikin, M. S., Costantino, G., Palyulin, V. A., Pellicciari, R. & Zefirov, N. S. Molecular modeling of the mGluR1 metabotropic glutamate receptor transmembrane domain and construction of the model of its dimer. Dokl Biochem Biophys 393, 341-345, doi:10.1023/b:dobi.0000010299.35247.fb (2003).

3. Bellucci, F. et al. Pharmacological evaluation of alpha and beta human tachykinin NK(2) receptor splice variants expressed in CHO cells. Eur J Pharmacol 499, 229-238, doi:10.1016/j.ejphar.2004.07.075 (2004).

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