A Role for the Chaperone Complex BAG3-HSPB8 in Actin Dynamics, Spindle Orientation and Proper Chromosome Segregation during Mitosis

被引：52

作者：

Fuchs, Margit ^{[1
,2
,3
]}

Luthold, Carole ^{[1
,2
,3
]}

Guilbert, Solenn M. ^{[1
,2
,3
]}

Varlet, Alice Anais ^{[1
,2
,3
]}

Lambert, Herman ^{[1
,2
,3
]}

Jette, Alexandra ^{[1
,2
,3
]}

Elowe, Sabine ^{[1
,4
,5
]}

Landry, Jacques ^{[1
,2
,3
]}

Lavoie, Josee N. ^{[1
,2
,3
]}

机构：

[1] Univ Laval, Ctr Rech Canc, Quebec City, PQ, Canada

[2] Univ Laval, Dept Biol Mol Biochim Med & Pathol, Quebec City, PQ, Canada

[3] Univ Laval, CHU Quebec, Ctr Rech, Oncol, Quebec City, PQ, Canada

[4] Univ Laval, CHU Quebec, Ctr Rech, Reprod,Perinatal Hlth & Child Hlth, Quebec City, PQ, Canada

[5] Univ Laval, Dept Pediat, Quebec City, PQ, Canada

来源：

PLOS GENETICS | 2015年 / 11卷 / 10期

基金：

加拿大健康研究院;

关键词：

HEAT-SHOCK PROTEINS; SRC FAMILY KINASES; CELL-ADHESION; SELECTIVE AUTOPHAGY; MISFOLDED PROTEINS; MITOTIC SPINDLE; BAG3; PHOSPHORYLATION; MACROAUTOPHAGY; REVEALS;

D O I：

10.1371/journal.pgen.1005582

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

The co-chaperone BAG3, in complex with the heat shock protein HSPB8, plays a role in protein quality control during mechanical strain. It is part of a multichaperone complex that senses damaged cytoskeletal proteins and orchestrates their seclusion and/or degradation by selective autophagy. Here we describe a novel role for the BAG3-HSPB8 complex in mitosis, a process involving profound changes in cell tension homeostasis. BAG3 is hyperphosphorylated at mitotic entry and localizes to centrosomal regions. BAG3 regulates, in an HSPB8-dependent manner, the timely congression of chromosomes to the metaphase plate by influencing the three-dimensional positioning of the mitotic spindle. Depletion of BAG3 caused defects in cell rounding at metaphase and dramatic blebbing of the cortex associated with abnormal spindle rotations. Similar defects were observed upon silencing of the autophagic receptor p62/SQSTM1 that contributes to BAG3-mediated selective autophagy pathway. Mitotic cells depleted of BAG3, HSPB8 or p62/SQSTM1 exhibited disorganized actin-rich retraction fibres, which are proposed to guide spindle orientation. Proper spindle positioning was rescued in BAG3-depleted cells upon addition of the lectin concanavalin A, which restores cortex rigidity. Together, our findings suggest the existence of a so-far unrecognized quality control mechanism involving BAG3, HSPB8 and p62/SQSTM1 for accurate remodelling of actin-based mitotic structures that guide spindle orientation.

引用

页数：32

共 83 条

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