biomolecules Review More Than Meets the Eye: Revisiting the Roles of Heat Shock Factor 4 in Health and Diseases Saiful Effendi Syafruddin *,† , Sheen Ling † , Teck Yew Low and M Aiman Mohtar UKM Medical Molecular Biology Institute, Universiti Kebangsaan Malaysia, Jalan Yaacob Latiff, Bandar Tun Razak, Kuala Lumpur 56000, Malaysia; [email protected] (S.L.); [email protected] (T.Y.L.); [email protected] (M.A.M.) * Correspondence: [email protected]; Tel.: +60-39145-9040 † These authors contributed equally to this work. Abstract: Cells encounter a myriad of endogenous and exogenous stresses that could perturb cellular physiological processes. Therefore, cells are equipped with several adaptive and stress-response machinery to overcome and survive these insults. One such machinery is the heat shock response (HSR) program that is governed by the heat shock factors (HSFs) family in response towards elevated temperature, free radicals, oxidants, and heavy metals. HSF4 is a member of this HSFs family that could exist in two predominant isoforms, either the transcriptional repressor HSFa or transcriptional activator HSF4b. HSF4 is constitutively active due to the lack of oligomerization negative regulator domain. HSF4 has been demonstrated to play roles in several physiological processes and not only limited to regulating the classical heat shock- or stress-responsive transcriptional programs. In this review, we will revisit and delineate the recent updates on HSF4 molecular properties. We also comprehensively discuss the roles of HSF4 in health and diseases, particularly in lens cell development, cataract formation, and cancer pathogenesis. Finally, we will posit the potential Citation: Syafruddin, S.E.; Ling, S.; direction of HSF4 future research that could enhance our knowledge on HSF4 molecular networks as Low, T.Y.; Mohtar, MA. More Than well as physiological and pathophysiological functions. Meets the Eye: Revisiting the Roles of Heat Shock Factor 4 in Health and Keywords: heat shock factors; cellular stress; cells development; transcription regulation; cataract; cancer Diseases. Biomolecules 2021, 11, 523. https://doi.org/10.3390/ biom11040523 1. Introduction Academic Editor: Jürg Bähler Cells are constantly being exposed to various forms of cellular stresses and external insults. Therefore, it is vital for them to mount appropriate responses and adapt to these Received: 8 March 2021 stresses in order to maintain proper cellular homeostasis and functions [1]. One of these Accepted: 29 March 2021 Published: 31 March 2021 responses include the activation of stress-associated responsive programs such as the heat shock response (HSR) [2], DNA damage response (DDR) [3], unfolded protein response (UPR) [4], hypoxic stress response [5], and oxidative stress response [6]. Since cells are de- Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in pendent on adaptive response machinery to cope with these insults, dysregulations in any published maps and institutional affil- of these stress-associated responsive programs have been implicated in many diseases such iations. as cardiovascular diseases, neurodegenerative diseases, inflammatory diseases, and can- cer [7,8]. The heat shock response program, in particular, plays a critical role in facilitating cell adaptation and survival in elevated temperature environments and in other stressful conditions. The cellular heat shock response program is tightly governed by a family of transcription factors known as the heat shock factors (HSFs). This review focuses solely Copyright: © 2021 by the authors. on heat shock factor 4 (HSF4), and we discuss the current understanding of the molecular Licensee MDPI, Basel, Switzerland. This article is an open access article properties and roles of HSF4 in health and diseases. Finally, we provide insights on the distributed under the terms and potential future HSF4 research direction to enhance our knowledge on HSF4 in general conditions of the Creative Commons and its functional relevance in both physiological and pathophysiological processes. Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). Biomolecules 2021, 11, 523. https://doi.org/10.3390/biom11040523 https://www.mdpi.com/journal/biomolecules BiomoleculesBiomolecules 2021 2021, 11, 11, x, x 2 2of of 18 18 Biomolecules 2021, 11, 523 2 of 18 2.2. Overview Overview of of the the Heat Heat Shock Shock Response Response (HSR) (HSR) 2. Overview of the Heat Shock Response (HSR) TheThe HSR HSR was was initially initially characterized characterized as as a a cellular cellular program program activated activated in in response response to to an an The HSR was initially characterized as a cellular program activated in response to increaseincrease in in temperature. temperature. It It was was later later discover discovereded that, that, in in addition addition to to elevated elevated temperatures, temperatures, an increase in temperature. It was later discovered that, in addition to elevated tempera- otherother stimuli stimuli such such as as free free radicals, radicals, oxidants, oxidants, and and heavy heavy metals metals are are able able to to trigger trigger the the HSR HSR tures, other stimuli such as free radicals, oxidants, and heavy metals are able to trigger the [9].[9]. The The heat heat shock shock proteins proteins (Hsps) (Hsps) are are down downstreamstream effectors effectors of of the the HSR HSR program. program. They They HSR [9]. The heat shock proteins (Hsps) are downstream effectors of the HSR program. actact as as molecular molecular chaperones chaperones to to facilitate facilitate prop properer protein protein folding folding as as well well as as to to prevent prevent the the They act as molecular chaperones to facilitate proper protein folding as well as to prevent accumulationaccumulation of of unfolded/misfolded unfolded/misfolded proteins proteins form formeded as as a a result result of of cellular cellular perturbations perturbations the accumulation of unfolded/misfolded proteins formed as a result of cellular perturba- or stressors [10]. Therefore, the stress response machinery serves to protect cells from pro- ortions stressors or stressors [10]. Therefore, [10]. Therefore, the stress the stressrespon responsese machinery machinery serves serves to protect to protect cells from cells frompro- teotoxic stress and severe cellular damages by maintaining proteostasis and normal func- teotoxicproteotoxic stress stress and severe and severe cellular cellular damages damages by maintaining by maintaining proteostasis proteostasis and normal and normal func- tions [10]. Like most cellular and molecular processes, the activation of HSR is tightly reg- tionsfunctions [10]. Like [10]. most Like mostcellular cellular and molecular and molecular processes, processes, the activation the activation of HSR of HSRis tightly is tightly reg- ulated by a specific transcription factor family known as heat shock factors (HSFs). Seven ulatedregulated by a byspecific a specific transcription transcription factor factor family family known known as heat as shock heat factors shock factors(HSFs). (HSFs).Seven members of the HSF family have been identified in mammals to date, which are: HSF1, membersSeven members of the HSF of the family HSF have family been have identi beenfied identified in mammals in mammals to date,to which date, are: which HSF1, are: HSF2,HSF1,HSF2, HSF3, HSF2,HSF3, HSF4, HSF3,HSF4, HSF5, HSF4,HSF5, HSFX, HSF5,HSFX, HSFX,and and HSFY HSFY and [1 HSFY[11].1]. The The [11 human]. human The human genome genome genome encodes encodes encodes all all these these all HSFstheseHSFs except HSFsexcept except for for HSF3, HSF3, for HSF3, which which which is is only only is onlyfound found found in in birds, birds, in birds, mice, mice, mice, and and andlizards lizards lizards [12–14]. [12–14]. [12–14 Phyloge- Phyloge-]. Phylo- neticgeneticnetic analysis analysis analysis of of ofhuman human human HSFs HSFs HSFs has has has revealed revealed revealed that that that HSF1, HSF1, HSF1, HSF4, HSF4, HSF4, and and and HSF2 HSF2 are are evolutionarily evolutionarily closerclosercloser to toto each eacheach other otherother in inin the thethe phylogenetic phylogenetic tree treetree (Figure (Figure 11). ).1). Collectively,Collectively, Collectively, HSF1,HSF1, HSF1, HSF2,HSF2, HSF2, andand and HSF4HSF4HSF4 share shareshare several severalseveral similar similarsimilar structural structuralstructural features featuresfeatures (i) (i)(i) a aa highly highly conserved conserved N-terminal N-terminal winged wingedwinged helix-turn-helixhelix-turn-helixhelix-turn-helix DNA-bindingDNA-binding domaindomain domain (DBD), (DBD), (DBD), (ii) (ii) (ii) a leucinea a leucine leucine zipper zipper zipper oligomerization oligomerization oligomerization domain do- do- mainthatmain comprisesthat that comprises comprises two heptadtwo two heptad heptad repeats repeats repeats HR-A/B HR-A/B HR-A/B (LZ1-3), (LZ1-3), (LZ1-3), (iii) a (iii) regulatory(iii) a a regulatory regulatory domain, domain, domain, and (iv) and and a (iv)C-terminus(iv) a a C-terminus C-terminus transactivation transactivation transactivation domain domain domain [15]. [15]. Besides,[15]. Besides, Besides, HSF1 HSF1 HSF1 and HSF2and and HSF2 HSF2 contain contain contain an additional an an addi- addi- tionalleucinetional leucine leucine zipper zipper zipper heptad heptad heptad repeat repeat HR-Crepeat HR-C (LZ4)HR-C at(LZ4) (LZ4) the C-terminusat at the the