Cilia-Localized Counterregulatory Signals as Drivers of Renal Cystogenesis

Abstract

Primary cilia play counterregulatory roles in cystogenesis—they inhibit cyst formation in the normal renal tubule but promote cyst growth when the function of polycystins is impaired. Key upstream cilia-specific signals and components involved in driving cystogenesis have remained elusive. Recent studies of the tubby family protein, Tubby-like protein 3 (TULP3), have provided new insights into the cilia-localized mechanisms that determine cyst growth. TULP3 is a key adapter of the intraflagellar transport complex A (IFT-A) in the trafficking of multiple proteins specifically into the ciliary membrane. Loss of TULP3 results in the selective exclusion of its cargoes from cilia without affecting their extraciliary pools and without disrupting cilia or IFT-A complex integrity. Epistasis analyses have indicated that TULP3 inhibits cystogenesis independently of the polycystins during kidney development but promotes cystogenesis in adults when polycystins are lacking. In this review, we discuss the current model of the cilia-dependent cyst activation (CDCA) mechanism in autosomal dominant polycystic kidney disease (ADPKD) and consider the possible roles of ciliary and extraciliary polycystins in regulating CDCA. We then describe the limitations of this model in not fully accounting for how cilia single knockouts cause significant cystic changes either in the presence or absence of polycystins. Based on available data from TULP3/IFT-A-mediated differential regulation of cystogenesis in kidneys with deletion of polycystins either during development or in adulthood, we hypothesize the existence of cilia-localized components of CDCA (cCDCA) and cilia-localized cyst inhibition (CLCI) signals. We develop the criteria for cCDCA/CLCI signals and discuss potential TULP3 cargoes as possible cilia-localized components that determine cystogenesis in kidneys during development and in adult mice.

A pathogenic variant of TULP3 causes renal and hepatic fibrocystic disease

“…Hepatorenal fibrocystic diseases are inherited disorders that involve developmental and degenerative abnormalities of the liver and kidneys (Gunay-Aygun, 2009). Many of the identified genes that are associated with renal or hepatic cystic and fibrotic diseases encode proteins that are localized to the primary cilium, strongly implicating these signaling organelles in regulating fibrocystic and cystic pathways (Tobin and Beales, 2009;Hildebrandt et al, 2011;Walker et al, 2022). Here we present two sisters with inherited fibrocystic kidney and liver disease attributable to a rare homozygous mutation in the ciliary protein TULP3.…”

Glis2 is an early effector of polycystin signaling and a target for therapy in polycystic kidney disease

“…The adult induced Cre recombinase expression pattern and natural history of polycystic kidney disease progression in this model has been described 19 , 36 . To identify differentially expressed transcripts that are most specifically correlated with cyst formation, we combined analysis from mice with three genotypes: Pkd1 single mutants (Pkd1 KO ) that are genetically destined to develop polycystic kidney disease 19 , Pkd1 and Kif3a (Pkd1 KO +cilia KO ) double knockouts that are protected from cyst growth despite inactivation of Pkd1 19 , 22 , and Pkd1 heterozygous mice that behave like wild type (“noncystic”) (Fig. 1a ).…”

“…Cyst growth was also suppressed in adult models of ADPKD following inactivation of Tulp3 , which affects the membrane associated protein composition of cilia without dismantling the organelle entirely 20 , 21 . These series of findings have suggested the existence of a cilia-dependent cyst activating (CDCA) pathway that can be defined as signaling pathway that is regulated by the polycystin complex located in cilia and whose full function requires the presence of intact cilia 19 , 22 . CDCA is a putative signaling pathway that requires structurally and functionally intact primary cilia to drive cyst growth following inactivation of polycystin-1 or polycystin-2.…”

Ciliary ARL13B inhibits developmental kidney cystogenesis in mouse

“…ARL13B localization in renal cilia requires TULP3, which is not the case in other cell types (Ferent et al, 2019; Hwang et al, 2019; Legue and Liem, 2019; Palicharla et al, 2023). Previous work on TULP3 proposed that it regulates a cilia-specific pathway that normally inhibits cystogenesis, termed the cilia localized cyst inhibitory (CLCI) pathway (Walker et al, 2022). Our findings here indicate that ciliary ARL13B is a likely component of the CLCI pathway during mouse development.…”