p38- and MK2-dependent signalling promotes stress-induced centriolar satellite remodelling via 14-3-3-dependent sequestration of CEP131/AZI1

Abstract

Centriolar satellites (CS) are small granular structures that cluster in the vicinity of centrosomes. CS are highly susceptible to stress stimuli, triggering abrupt displacement of key CS factors. Here we discover a linear p38-MK2-14-3-3 signalling pathway that specifically targets CEP131 to trigger CS remodelling after cell stress. We identify CEP131 as a substrate of the p38 effector kinase MK2 and pinpoint S47 and S78 as critical MK2 phosphorylation sites in CEP131. Ultraviolet-induced phosphorylation of these residues generates direct binding sites for 14-3-3 proteins, which sequester CEP131 in the cytoplasm to block formation of new CS, thereby leading to rapid depletion of these structures. Mutating S47 and S78 in CEP131 is sufficient to abolish stress-induced CS reorganization, demonstrating that CEP131 is the key regulatory target of MK2 and 14-3-3 in these structures. Our findings reveal the molecular mechanism underlying dynamic CS remodelling to modulate centrosome functions on cell stress.

Regulation of centriolar satellite integrity and its physiology

“…In fact, satellite remodelling upon stresses requires p38; activated p38 leads to enhanced interaction between PCM1 and CEP131/AZI1 in the cytoplasm away from the pericentriolar region, where these two proteins are normally localised. p38 activates the downstream kinase MK2, which in turn phosphorylates CEP131/AZI1, thereby creating a binding pocket for the phospho-adaptor 14-3-3 [111]. 14-3-3-associated CEP131/AZI1 binds tightly to PCM1, which results in the blockage of new satellite formation (Fig.…”

“…On one hand, it results in the remodelling of centriolar satellites, in which PCM1 as well as CEP131/AZI1 and CEP290 becomes dispersed away from the pericentriolar region, and yet promotes ciliogenesis [58, 111]. On the other hand, it leads to centrosome overproduction using centriolar satellites as intermediate precursors (Fig.…”

“…One lies in the DNA-damaging methods and downstream pathways that are activated. The former studies [58, 111] used UV treatment, which activates the p38-SAPK pathway, while the latter study [114] used IR and Bleomycin, which activate the CHK1-DNA damage checkpoint pathway. The second difference is the experimental timeline.…”

“…The second difference is the experimental timeline. In the former reports [58, 111], acute responses were observed (1 h after UV treatment), while in the latter report [114], cells were observed at much later time points (24–72 h after irradiation). In any case, collectively, these findings uncovered the hitherto unknown spatiotemporal dynamics of centriolar satellite organisation upon exposure to various types of cellular stresses.…”

“…Thus, centriolar satellites play both positive and negative roles in ciliogenesis. As mentioned earlier, various cellular stresses promote ciliogenesis through satellite remodelling, in which OFD1 forms non-canonical centriolar satellites without PCM1 [58, 111]. Given the inhibitory role of OFD1 in ciliogenesis, OFD1-containing satellites assembled under acute stress conditions may represent the inactive form of OFD1 (e.g.…”