Integrated signaling and transcriptome analysis reveals Src family kinase individualities and novel pathways controlled by their constitutive activity

被引:1
作者
Koutras, Nikolaos [1 ]
Morfos, Vasileios [1 ]
Konnaris, Kyriakos [1 ]
Kouvela, Adamantia [1 ]
Shaukat, Athanasios-Nasir [1 ]
Stathopoulos, Constantinos [1 ]
Stamatopoulou, Vassiliki [1 ]
Nika, Konstantina [1 ]
机构
[1] Univ Patras, Sch Med, Dept Biochem, Patras, Greece
来源
FRONTIERS IN IMMUNOLOGY | 2023年 / 14卷
关键词
Src family kinases; Lck; Lyn; B-cell receptor; signal transduction; transcriptomics; ER-phagy; ENDOPLASMIC-RETICULUM STRESS; LYN KINASE; AID EXPRESSION; ACTIVATION; AUTOPHAGY; LCK; DEGRADATION; CELLS; CLL;
D O I
10.3389/fimmu.2023.1224520
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
The Src family kinases (SFKs) Lck and Lyn are crucial for lymphocyte development and function. Albeit tissue-restricted expression patterns the two kinases share common functions; the most pronounced one being the phosphorylation of ITAM motifs in the cytoplasmic tails of antigenic receptors. Lck is predominantly expressed in T lymphocytes; however, it can be ectopically found in B-1 cell subsets and numerous pathologies including acute and chronic B-cell leukemias. The exact impact of Lck on the B-cell signaling apparatus remains enigmatic and is followed by the long-lasting question of mechanisms granting selectivity among SFK members. In this work we sought to investigate the mechanistic basis of ectopic Lck function in B-cells and compare it to events elicited by the predominant B-cell SFK, Lyn. Our results reveal substrate promiscuity displayed by the two SFKs, which however, is buffered by their differential susceptibility toward regulatory mechanisms, revealing a so far unappreciated aspect of SFK member-specific fine-tuning. Furthermore, we show that Lck- and Lyn-generated signals suffice to induce transcriptome alterations, reminiscent of B-cell activation, in the absence of receptor/co-receptor engagement. Finally, our analyses revealed a yet unrecognized role of SFKs in tipping the balance of cellular stress responses, by promoting the onset of ER-phagy, an as yet completely uncharacterized process in B lymphocytes.
引用
收藏
页数:17
相关论文
共 55 条
[1]   The Galaxy platform for accessible, reproducible and collaborative biomedical analyses: 2018 update [J].
Afgan, Enis ;
Baker, Dannon ;
Batut, Berenice ;
van den Beek, Marius ;
Bouvier, Dave ;
Cech, Martin ;
Chilton, John ;
Clements, Dave ;
Coraor, Nate ;
Gruening, Bjoern A. ;
Guerler, Aysam ;
Hillman-Jackson, Jennifer ;
Hiltemann, Saskia ;
Jalili, Vahid ;
Rasche, Helena ;
Soranzo, Nicola ;
Goecks, Jeremy ;
Taylor, James ;
Nekrutenko, Anton ;
Blankenberg, Daniel .
NUCLEIC ACIDS RESEARCH, 2018, 46 (W1) :W537-W544
[2]   Trimmomatic: a flexible trimmer for Illumina sequence data [J].
Bolger, Anthony M. ;
Lohse, Marc ;
Usadel, Bjoern .
BIOINFORMATICS, 2014, 30 (15) :2114-2120
[3]   Beyond TCR Signaling: Emerging Functions of Lck in Cancer and Immunotherapy [J].
Bommhardt, Ursula ;
Schraven, Burkhart ;
Simeoni, Luca .
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 2019, 20 (14)
[4]   The Src-family Kinase Lyn in Immunoreceptor Signaling [J].
Brian, Ben F. ;
Freedman, Tanya S. .
ENDOCRINOLOGY, 2021, 162 (10)
[5]   Progressively impaired proteasomal capacity during terminal plasma cell differentiation [J].
Cenci, S ;
Mezghrani, A ;
Cascio, P ;
Bianchi, G ;
Cerruti, F ;
Fra, A ;
Lelouard, H ;
Masciarelli, S ;
Mattioli, L ;
Oliva, L ;
Orsi, A ;
Pasqualetto, E ;
Pierre, P ;
Ruffato, E ;
Tagliavacca, L ;
Sitia, R .
EMBO JOURNAL, 2006, 25 (05) :1104-1113
[6]  
Corcoran LM, 2005, CURR TOP MICROBIOL, V290, P105
[7]   UNG protects B cells from AID-induced telomere loss [J].
Cortizas, Elena M. ;
Zahn, Astrid ;
Safavi, Shiva ;
Reed, Joseph A. ;
Vega, Francisco ;
Di Noia, Javier M. ;
Verdun, Ramiro E. .
JOURNAL OF EXPERIMENTAL MEDICINE, 2016, 213 (11) :2459-2472
[8]   Regulation of AID expression in the immune response [J].
Crouch, Elizabeth E. ;
Li, Zhiyu ;
Takizawa, Makiko ;
Fichtner-Feigl, Stefan ;
Gourzi, Polyxeni ;
Montano, Carolina ;
Feigenbaum, Lionel ;
Wilson, Patrick ;
Janz, Siegfried ;
Papavasiliou, F. Nina ;
Casellas, Rafael .
JOURNAL OF EXPERIMENTAL MEDICINE, 2007, 204 (05) :1145-1156
[9]   B Cell Responses: Cell Interaction Dynamics and Decisions [J].
Cyster, Jason G. ;
Allen, Christopher D. C. .
CELL, 2019, 177 (03) :524-540
[10]   Linking of autophagy to ubiquitin-proteasome system is important for the regulation of endoplasmic reticulum stress and cell viability [J].
Ding, Wen-Xing ;
Ni, Hong-Min ;
Gao, Wentao ;
Yoshimori, Tamotsu ;
Stolz, Donna B. ;
Ron, David ;
Yin, Xiao-Ming .
AMERICAN JOURNAL OF PATHOLOGY, 2007, 171 (02) :513-524