Structure, dynamics and functions of UBQLNs: at the crossroads of protein quality control machinery

Abstract

Cells rely on protein homeostasis to maintain proper biological functions. Dysregulation of protein homeostasis contributes to the pathogenesis of many neurodegenerative diseases and cancers. Ubiquilins (UBQLNs) are versatile proteins that engage with many components of protein quality control (PQC) machinery in cells. Disease-linked mutations of UBQLNs are most commonly associated with amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and other neurodegenerative disorders. UBQLNs play well-established roles in PQC processes, including facilitating degradation of substrates through the ubiquitin–proteasome system (UPS), autophagy, and endoplasmic-reticulum-associated protein degradation (ERAD) pathways. In addition, UBQLNs engage with chaperones to sequester, degrade, or assist repair of misfolded client proteins. Furthermore, UBQLNs regulate DNA damage repair mechanisms, interact with RNA-binding proteins (RBPs), and engage with cytoskeletal elements to regulate cell differentiation and development. Important to the myriad functions of UBQLNs are its multidomain architecture and ability to self-associate. UBQLNs are linked to numerous types of cellular puncta, including stress-induced biomolecular condensates, autophagosomes, aggresomes, and aggregates. In this review, we focus on deciphering how UBQLNs function on a molecular level. We examine the properties of oligomerization-driven interactions among the structured and intrinsically disordered segments of UBQLNs. These interactions, together with the knowledge from studies of disease-linked mutations, provide significant insights to UBQLN structure, dynamics and function.

RTL8 promotes nuclear localization of UBQLN2 to subnuclear compartments associated with protein quality control

“…Other UBQLN family members, including UBQLN1 and UBQLN4, share conserved structural domains with UBQLN2 except for the proline-rich repeat region (PXX) that is unique to UBQLN2 [47] (Fig. 5A).…”

Previously uncharacterized interactions between the folded and intrinsically disordered domains impart asymmetric effects on UBQLN2 phase separation

“…One such shuttle protein is ubiquilin‐2 (UBQLN2), which undergoes liquid–liquid phase separation (LLPS) and is recruited to cytoplasmic stress granules, biomolecular condensates with liquid‐like properties 7,8 . As Ub binds to UBQLN2 UBA to drive disassembly of UBQLN2 condensates, we hypothesize that LLPS contributes to UBQLN2's functionality in UPS and protein quality control (PQC) 9,10 . Recently, other UBL‐UBA shuttle proteins, including hHR23B and p62/SQSTM1, have been reported to undergo LLPS in the presence of polyUb chains 11–13 .…”

“…The middle IDR of UBQLN2, consisting of residues 109–576, includes the STI1‐I, STI1‐II, and PXX regions connected by disordered linkers. The low‐complexity STI1 regions are presumed to mediate interactions with chaperone proteins such as HSP70, autophagosomal components such as LC3, and even client proteins 10,20–22 . However, specific interactions involving the IDR are largely unknown.…”

Previously uncharacterized interactions between the folded and intrinsically disordered domains impart asymmetric effects on UBQLN2 phase separation

“…One such shuttle protein is ubiquilin-2 (UBQLN2), which undergoes liquid-liquid phase separation and is recruited to cytoplasmic stress granules, biomolecular condensates with liquid-like properties (Alexander et al, 2018; Dao et al, 2018). As Ub binds to UBQLN2 UBA to drive disassembly of UBQLN2 condensates, we hypothesize that LLPS contributes to UBQLN2’s functionality in UPS and protein quality control (PQC) (Dao and Castañeda, 2020; Zheng et al, 2020). Recently, other UBL-UBA shuttle proteins including hHR23B and p62/SQSTM1 have been reported to undergo LLPS in the presence of polyUb chains (Sun et al, 2018; Yasuda et al, 2020; Zaffagnini et al, 2018).…”

“…The middle IDR of UBQLN2, consisting of residues 109-576, includes the STI1-I, STI1-II and PXX regions connected by disordered linkers. The STI1 regions are presumed to mediate interactions with chaperone proteins such as HSP70, autophagosomal components such as LC3, and even client proteins (Hjerpe et al, 2016; Kurlawala et al, 2017; Lee et al, 2013; Zheng et al, 2020). However, specific interactions involving the IDR are largely unknown.…”