Targeting an anchored phosphatase-deacetylase unit restores renal ciliary homeostasis

Abstract

Pathophysiological defects in water homeostasis can lead to renal failure. Likewise, common genetic disorders associated with abnormal cytoskeletal dynamics in the kidney collecting ducts and perturbed calcium and cAMP signaling in the ciliary compartment contribute to chronic kidney failure. We show that collecting ducts in mice lacking the A-Kinase anchoring protein AKAP220 exhibit enhanced development of primary cilia. Mechanistic studies reveal that AKAP220-associated protein phosphatase 1 (PP1) mediates this phenotype by promoting changes in the stability of histone deacetylase 6 (HDAC6) with concomitant defects in actin dynamics. This proceeds through a previously unrecognized adaptor function for PP1 as all ciliogenesis and cytoskeletal phenotypes are recapitulated in mIMCD3 knock-in cells expressing a phosphatase-targeting defective AKAP220-ΔPP1 mutant. Pharmacological blocking of local HDAC6 activity alters cilia development and reduces cystogenesis in kidney-on-chip and organoid models. These findings identify the AKAP220-PPI-HDAC6 pathway as a key effector in primary cilia development.

Recruitment of BAG2 to DNAJ-PKAc scaffolds promotes cell survival and resistance to drug-induced apoptosis in fibrolamellar carcinoma

“… 18 , 19 AKAPs also integrate subcellular signals from other kinases and effector enzymes at sites proximal to their substrates. 20 – 23 Signaling through AKAPs limits the range and duration of information relay within cells. 24 – 26 In this report, we show that DNAJ-PKAc preferentially interacts with a particular spectrum of binding partners.…”

Transcriptomic and epigenomic consequences of heterozygous loss of function mutations inAKAP11, the first large-effect shared risk gene for bipolar disorder and schizophrenia

“…It has been shown that the AKAP11-involved cAMP/PKA signaling inhibits gene transcription by phosphorylating HDACs, such as HDAC5, and preventing their export from the nucleus 25 . In addition, AKAP11-PP1 complex can affect HDAC6 stability 85 . Moreover, AKAP11-PKA-regulated GSK3B, one of the molecular targets of lithium, which is the most common medication to prevent recurrences of both manic and depressive episodes in BD patients [18][19][20][21] , has been suggested to be involved in the regulation of HDAC6 activity through phosphorylation events 26 .…”

Recruitment of BAG2 to DNAJ-PKAc scaffolds promotes cell survival and resistance to drug-induced apoptosis in fibrolamellar carcinoma

“…Compartmentalization though association with A-kinase anchoring proteins (AKAPs) is a mechanism that imparts specificity to PKA signaling 18,19 . AKAPs also integrate subcellular signals from other kinases and effector enzymes at sites proximal to their substrates [20][21][22][23] . Signaling through AKAPs limits the range and duration of information relay within cells [24][25][26] .…”