Recovering rRNA processing after heat shock

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Science Signaling  07 Feb 2017:
Vol. 10, Issue 465, eaam9083
DOI: 10.1126/scisignal.aam9083

NF-κB repressing factor controls localization and activation of an rRNA processing protein in heat stress response.

Increased temperature causes cells to initiate heat shock responses in the nucleus, including activating heat shock transcription factors (HSFs), which bind to heat shock elements (HSEs) to promote the expression of genes encoding heat shock proteins (HSPs). Many HSPs are molecular chaperones that stabilize proteins, which can unfold during heat stress, but some genes induced by heat shock encode proteins that are not molecular chaperones. Coccia et al. found that HSF1, a master transcription factor activated by heat stress, promoted the expression of the gene encoding nuclear factor κB repressing factor (NKRF), which enabled ribosomal RNA (rRNA) processing during recovery from temperature stress. HeLa cells exposed to 43°C (or 39°C, to mimic fever conditions) exhibited increased NKRF mRNA, a response lacking in HSF1-silenced cells. The promoter region of the gene encoding NKRF contains two putative HSEs, one of which promoted transcription in response to heat stress in a reporter assay using wild-type HeLa cells but not HSF1-silenced cells. However, the amount of NKRF protein decreased during the heat shock period and took several hours after the temperature was returned to 37°C to recover in abundance, suggesting that NKRF mRNA accumulated during heat shock and then was translated during the recovery period. NKRF shifted from the soluble fraction in nonstressed cells to the insoluble fraction in heat-stressed cells, which may trigger its degradation. NKRF colocalized with the 5ʹ-to-3ʹ exonuclease XRN2, which converts 32.5S pre-rRNA into 32S rRNA and degrades the residual fragments in the nucleolus. Both XRN2 and NKRF moved from the nucleolus to the nucleoplasm during heat stress and returned to the nucleolus within 3 hours after the return to 37°C. The relocalization of XRN2 to the nucleolus during recovery from heat stress required NKRF. Silencing NKRF under normal temperature resulted in the accumulation of unprocessed pre-rRNA and rRNA fragments. In heat-stressed wild-type cells, unprocessed pre-rRNA accumulated during heat stress but decreased after cells were returned to normal temperature, consistent with inhibition of processing followed by resumption. In NKRF-silenced cells, the amount of unprocessed rRNA remained high after cells were returned to normal temperature and cell death increased. The authors propose a model wherein HSF1 induces transcription of NKRF during heat shock, providing a pool of transcript for translation upon the return to normal temperature and thereby enabling the return of XNR2 to the nucleolus and reactivation of pre-rRNA processing.

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