TDP-43 Toxicity in Yeast Is Associated with a Reduction in Autophagy, and Deletions of TIP41 and PBP1 Counteract These Effects.
TDP-43 Toxicity in Yeast Is Associated with a Reduction in Autophagy, and Deletions of TIP41 and PBP1 Counteract These Effects.
复制标题
酵母中TDP-43的毒性与自噬的降低有关，而TIP41和PBP1的缺失抵消了这些效果。
DOI：
10.3390/v14102264
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发表时间：
2022-10-15
期刊：
影响因子：
--
通讯作者：
Liebman SW
中科院分区：
文献类型：
--
作者：
Park SK;Park S;Liebman SW
当人TDP-43在酵母中过表达时，它是有毒的并形成细胞质聚集体。这种毒性的机制尚不清楚。在酵母系统中对TDP-43毒性调节剂进行遗传筛选，先前鉴定出增强TDP-43毒性的蛋白质，包括PBP 1。在酵母中确定PBP 1的缺失降低了TDP-43的毒性，而过表达增强了毒性，导致发现其人类同源物ATXN 2与ALS风险相关。因此，酵母系统与人类疾病有关。我们现在表明，删除一个新的酵母基因，tip 41 Δ，同样抑制TDP-43的毒性。我们还发现TDP-43过表达和毒性与自噬减少有关。这与其他系统中增加自噬降低TDP-43毒性的发现一致，并且与当TDP-43在酵母中过表达时增强自噬的报道相反。有趣的是，我们发现PBP 1和TIP 41的缺失降低了TDP-43的毒性，消除了TDP-43对自噬的抑制作用。这表明在酵母中表达的TDP-43的毒性部分是由于其抑制自噬，并且PBP 1和TIP 41的缺失可以通过阻止TDP-43抑制自噬来降低TDP-43的毒性。
When human TDP-43 is overexpressed in yeast it is toxic and forms cytoplasmic aggregates. The mechanism of this toxicity is unknown. Genetic screens for TDP-43 toxicity modifiers in the yeast system previously identified proteins, including PBP1, that enhance TDP-43 toxicity. The determination in yeast that deletion of PBP1 reduces TDP-43 toxicity while overexpression enhances toxicity, led to the discovery that its human homolog, ATXN2, is associated with ALS risk. Thus, the yeast system has relevance to human disease. We now show that deletion of a new yeast gene, tip41Δ, likewise suppresses TDP-43 toxicity. We also found that TDP-43 overexpression and toxicity is associated with reduced autophagy. This is consistent with findings in other systems that increasing autophagy reduces TDP-43 toxicity and is in contrast to a report of enhanced autophagy when TDP-43 was overexpressed in yeast. Interestingly, we found that deletions of PBP1 and TIP41, which reduced TDP-43 toxicity, eliminated TDP-43′s inhibition of autophagy. This suggests that toxicity of TDP-43 expressed in yeast is in part due to its inhibition of autophagy and that deletions of PBP1 and TIP41 may reduce TDP-43 toxicity by preventing TDP-43 from inhibiting autophagy.
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影响因子：
9.8
作者：
Ju S;Tardiff DF;Han H;Divya K;Zhong Q;Maquat LE;Bosco DA;Hayward LJ;Brown RH Jr;Lindquist S;Ringe D;Petsko GA
通讯作者：
Petsko GA
影响因子：
14.8
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影响因子：
16
作者：
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通讯作者：
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影响因子：
4.5
作者：
Park SK;Hong JY;Arslan F;Kanneganti V;Patel B;Tietsort A;Tank EMH;Li X;Barmada SJ;Liebman SW
通讯作者：
Liebman SW
DOI：
10.1083/jcb.200112104
发表时间：
2002-06-10
期刊：
The Journal of cell biology
影响因子：
--
作者：
Meriin AB;Zhang X;He X;Newnam GP;Chernoff YO;Sherman MY
通讯作者：
Sherman MY